Study of Pembrolizumab (MK-3475) Versus Investigator's Choice of Chemotherapy for Participants With Advanced Esophageal/Esophagogastric Junction Carcinoma That Progressed After First-Line Therapy (MK-3475-181/KEYNOTE-181)-China Extension Study

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03933449
• Collaborator: (none)
• Enrollment: 123
• Locations: 23
• Arms: 2
• Actual Duration (Months): 62.5
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

In the China extension study, Chinese participants with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ) that has progressed after first-line standard therapy will be randomized to receive either single agent pembrolizumab or the Investigator's choice of chemotherapy with paclitaxel, docetaxel, or irinotecan.

The primary extension study hypothesis is that treatment with pembrolizumab will prolong overall survival (OS) as compared to treatment with chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Carcinoma; Esophagogastric Junction Carcinoma	Biological: pembrolizumab; Drug: paclitaxel; Drug: docetaxel; Drug: irinotecan	Phase 3

Detailed Description

The China extension study will include participants previously enrolled in China in the global study for MK-3475-181 (NCT02564263) plus those enrolled during the China extension enrollment period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 123 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Open-Label Study of Single Agent Pembrolizumab vs Physicians' Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in Subjects With Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus That Have Progressed After First-Line Standard Therapy (KEYNOTE-181)
• Actual Study Start Date: Dec 29, 2016
• Actual Primary Completion Date: Feb 13, 2019
• Actual Study Completion Date: Mar 14, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Biological: pembrolizumab; IV infusion; Other Names: KEYTRUDA® MK-3475
Active Comparator: Chemotherapy Participants receive Investigator's choice of chemotherapy: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 2 years).	Drug: paclitaxel; IV infusion; Other Names: TAXOL® ; Drug: docetaxel; IV infusion; Other Names: TAXOTERE® ; Drug: irinotecan; IV infusion; Other Names: CAMPTOSAR®

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) in All Participants [From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)]

   OS was defined as the time from randomization to death due to any cause. Median OS in all participants is presented.

2. Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10) [From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)]

   OS was defined as the time from randomization to death due to any cause. Median OS in participants with a PD-L1 CPS ≥10 is presented.

3. Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus [From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)]

   OS was defined as the time from randomization to death due to any cause. Median OS in participants with SCC of the esophagus is presented.

Secondary Outcome Measures

1. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants [From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)]

   ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1 by central imaging vendor review. The percentage of all participants who experienced a CR or PR is presented.

2. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10) [From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)]

   ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1 by central imaging vendor review. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR is presented.

3. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus [From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)]

   ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1 by central imaging vendor review. The percentage of participants with SCC of the esophagus who experienced a CR or PR is presented.

4. Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants [From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)]

   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 RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by central imaging vendor review per RECIST 1.1 in all participants is presented.

5. Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10) [From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)]

   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 RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by central imaging vendor review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10.

6. Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus [From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)]

   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 RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by central imaging vendor review per RECIST 1.1 is presented for participants with SCC of the esophagus.

7. Number of Participants Experiencing an Adverse Event (AE) [From first dose of study treatment through end-of-trial analysis data cutoff date of 31-Dec-2021 (Up to approximately 5 years)]

   An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who experienced ≥1 AE will be presented.

8. Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE) [From first dose of study treatment through to end-of-trial analysis data cutoff date of 31-Dec-2021 (Up to approximately 5 years)]

   An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE will be presented.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically- or cytologically-confirmed diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ

• Metastatic disease or locally advanced, unresectable disease

• Life expectancy of greater than 3 months

• Measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1

• Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale

• Documented radiographic or clinical disease progression on no more or less than one previous line of standard therapy

• Can provide either a newly obtained or archival tumor tissue sample for intra-tumoral immune-related testing and for anti-programmed cell death (PD)-1

• Participants of reproductive potential must be willing to use adequate contraception for the course of the study through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel, docetaxel or irinotecan

• Adequate organ function

Exclusion Criteria:

• Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study medication

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

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

• Known central nervous system (CNS) metastases and/or carcinomatous meningitis (includes past history or current metastasis)

• Has received prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or not recovered from adverse events due to a previously administered agent

• Has had a severe hypersensitivity reaction to treatment with another mAb

• Prior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1), or anti-PD-L2 agent, or previously participated in Merck pembrolizumab (MK-3475) study

• Has a known additional malignancy that has progressed or required active treatment within the last 5 years with the exception of curatively treated basal cell and squamous cell carcinoma of the skin and/or curatively resected in-situ cervical and/or breast cancers, and in-situ or intra-mucosal pharyngeal cancer

• Received a live vaccine within 30 days of the first dose of study medication

• Known history of Human Immunodeficiency Virus (HIV) infection

• Known history of or is positive for hepatitis B (hepatitis B surface antigen reactive) or known active hepatitis C (hepatitis C virus RNA or hepatitis C antibody is detected)

• History of non-infectious pneumonitis that required steroids or current pneumonitis

• Active infection requiring systemic therapy

• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study

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

• Known allergy, hypersensitivity, or contraindication to paclitaxel, docetaxel, or irinotecan or any components used in their preparation

• Experienced weight loss > 10% over approximately 2 months prior to first dose of study therapy

• Has ascites or pleural effusion by physical exam

• Has experienced documented objective radiographic or clinical disease progression during or after receiving more than 1 line of therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anhui Provincial Hospital ( Site 0708)	Hefei	Anhui	China	230001
2	The First Affiliated Hospital of Anhui Medical University ( Site 0707)	Hefei	Anhui	China	230022
3	Harbin Medical University Cancer Hospital ( Site 0714)	Harbin	Heilongjiang	China	150081
4	Wuhan Tongji Hospital ( Site 0724)	Wuhan	Hubei	China	430030
5	Hunan Cancer Hospital ( Site 0722)	Changsha	Hunan	China	410013
6	Jiangsu Cancer Hospital (Site 0704)	Nanjing	Jiangsu	China	210000
7	PLA Cancer Centre of Nanjing Bayi Hospital ( Site 0706)	Nanjing	Jiangsu	China	210002
8	The First Hospital Of Jilin University ( Site 0719)	Chang chun	Jilin	China	130021
9	Jilin Cancer Hospital ( Site 0718)	Changchun	Jilin	China	130012
10	Zhejiang Cancer Hospital ( Site 0726)	Hangzhou	Zhejiang	China	310022
11	Beijing Cancer Hospital ( Site 0700)	Beijing		China	100042
12	Chinese PLA General Hospital (Site 0703)	Beijing		China	100042
13	Peking Union Medical College Hospital ( Site 0712)	Beijing		China	100730
14	Fujian Medical University Union Hospital ( Site 0721)	Fuzhou		China	350001
15	Fujian Province Cancer Hospital ( ( Site 0717)	Fuzhou		China	350014
16	The Second Affiliated Hospital of Zhejiang University School of Medicine ( Site 0705)	Hangzhou		China	310009
17	Sir Sun Sun Shaw Hosp, Zhejiang Univ,Oncology dept. ( Site 0720)	Hangzhou		China	310016
18	The Affiliated Hospital of Qingdao University ( Site 0709)	Qingdao		China	266003
19	Ruijin Hospital, Shanghai Jiaotong University ( Site 0701)	Shanghai		China	200025
20	Shanghai Chest Hospital ( Site 0727)	Shanghai		China	200030
21	Fudan University Shanghai Cancer Center ( Site 0723)	Shanghai		China	200032
22	Zhongshan Hospital affiliated to Fudan University ( Site 0715)	Shanghai		China	200032
23	Henan Cancer Hospital ( Site 0725)	Zhengzhou		China	450008

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 29, 2017

More Information

Additional Information:

• Merck Oncology Clinical Trial Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03933449
• Other Study ID Numbers: 3475-181 China Extension; 163145; MK-3475-181; KEYNOTE-181
• First Posted: May 1, 2019
• Last Update Posted: Aug 17, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Merck Sharp & Dohme LLC: Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1); Programmed Death-Ligand 2 (PDL2, PD-L2); Gene expression profiling (GEP)
• Additional relevant MeSH terms: Carcinoma; Esophageal Neoplasms; Paclitaxel; Docetaxel; Pembrolizumab; Irinotecan

Study Results

Participant Flow

Recruitment Details	This results disclosure is based on a data cutoff date of 13-Feb-2019, at which time 26 participants were ongoing in the study.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Period Title: Overall Study
STARTED	62	61
Treated	62	59
COMPLETED	0	0
NOT COMPLETED	62	61

Baseline Characteristics

Arm/Group Title	Pembrolizumab	Chemotherapy	Total
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.	Total of all reporting groups
Overall Participants	62	61	123
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.1 (7.0)	59.6 (7.0)	59.9 (7.0)
Sex: Female, Male (Count of Participants)
Female	5 8.1%	3 4.9%	8 6.5%
Male	57 91.9%	58 95.1%	115 93.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	62 100%	61 100%	123 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	62 100%	61 100%	123 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Programmed Death-Ligand 1 (PD-L1) Status: Combined Positive Score (CPS) (Count of Participants)
PD-L1 CPS ≥10	25 40.3%	29 47.5%	54 43.9%
PD-L1 CPS <10	35 56.5%	31 50.8%	66 53.7%
Not Evaluable	2 3.2%	1 1.6%	3 2.4%
Tumor Histology (Count of Participants)
Squamous cell carcinoma	60 96.8%	59 96.7%	119 96.7%
Adenocarcinoma of esophagus & EGJ Siewert type I	2 3.2%	2 3.3%	4 3.3%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) in All Participants
Description	OS was defined as the time from randomization to death due to any cause. Median OS in all participants is presented.
Time Frame	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Measure Participants	62	61
Median (95% Confidence Interval) [Months]	8.4	5.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments	One-sided p-value based on log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.36 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox regression model with treatment as a covariate

2. Primary Outcome

Title	Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
Description	OS was defined as the time from randomization to death due to any cause. Median OS in participants with a PD-L1 CPS ≥10 is presented.
Time Frame	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with a PD-L1 CPS ≥10. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Measure Participants	25	29
Median (95% Confidence Interval) [Months]	12.0	5.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments	One-sided p-value based on log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox regression model with treatment as a covariate

3. Primary Outcome

Title	Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
Description	OS was defined as the time from randomization to death due to any cause. Median OS in participants with SCC of the esophagus is presented.
Time Frame	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with SCC of the esophagus. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Measure Participants	60	59
Median (95% Confidence Interval) [Months]	8.4	5.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments	One-sided p-value based on log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.37 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox regression model with treatment as a covariate

4. Secondary Outcome

Title	Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
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: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1 by central imaging vendor review. The percentage of all participants who experienced a CR or PR is presented.
Time Frame	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants who experienced a confirmed response (CR or PR). Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Measure Participants	62	61
Number (95% Confidence Interval) [Percentage of Participants]	16.1 26%	3.3 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0084
	Comments	One-sided p-value for testing. H0: difference in %=0 versus H1: difference in %>0.
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	12.9
	Confidence Interval	(2-Sided) 95%; 2.7 to 24.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
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: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1 by central imaging vendor review. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR is presented.
Time Frame	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with a PD-L1 CPS ≥10 who experienced a confirmed response (CR or PR). Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Measure Participants	25	29
Number (95% Confidence Interval) [Percentage of Participants]	24.0 38.7%	6.9 11.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0403
	Comments	One-sided p-value for testing. H0: difference in %=0 versus H1: difference in %>0.
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	17.1
	Confidence Interval	(2-Sided) 95%; -2.3 to 38.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
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: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1 by central imaging vendor review. The percentage of participants with SCC of the esophagus who experienced a CR or PR is presented.
Time Frame	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with SCC of the esophagus who experienced a confirmed response (CR or PR). Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Measure Participants	60	59
Number (95% Confidence Interval) [Percentage of Participants]	16.7 26.9%	3.4 5.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0083
	Comments	One-sided p-value for testing. H0: difference in %=0 versus H1: difference in %>0.
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	13.3
	Confidence Interval	(2-Sided) 95%; 2.8 to 25.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
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 RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by central imaging vendor review per RECIST 1.1 in all participants is presented.
Time Frame	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Measure Participants	62	61
Median (95% Confidence Interval) [Months]	2.5	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.177
	Comments	One-sided p-value based on log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox regression model with treatment as a covariate

8. Secondary Outcome

Title	Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
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 RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by central imaging vendor review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10.
Time Frame	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with a PD-L1 CPS ≥10. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Measure Participants	25	29
Median (95% Confidence Interval) [Months]	4.0	4.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.238
	Comments	One-sided p-value based on log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.44 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox regression model with treatment as a covariate

9. Secondary Outcome

Title	Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
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 RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by central imaging vendor review per RECIST 1.1 is presented for participants with SCC of the esophagus.
Time Frame	From randomization through final analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

The efficacy analysis population consisted of all randomized participants with SCC of the esophagus. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).	Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
Measure Participants	60	59
Median (95% Confidence Interval) [Months]	2.3	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.171
	Comments	One-sided p-value based on log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox regression model with treatment as a covariate

10. Secondary Outcome

Title	Number of Participants Experiencing an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who experienced ≥1 AE will be presented.
Time Frame	From first dose of study treatment through end-of-trial analysis data cutoff date of 31-Dec-2021 (Up to approximately 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE will be presented.
Time Frame	From first dose of study treatment through to end-of-trial analysis data cutoff date of 31-Dec-2021 (Up to approximately 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From first dose of study treatment through analysis data cutoff date of 13-Feb-2019 (Up to approximately 24 months)
Adverse Event Reporting Description	Safety: All treated participants; All-Cause Mortality: All randomized participants Per protocol, disease progression of cancer under study was not considered an adverse event (AE) unless considered related to study treatment. Thus, Medical Dictionary for Regulatory Activities (MedDRA) preferred terms "Neoplasm progression", "Malignant neoplasm progression" & "Disease progression" not related to study treatment are excluded as AEs.
Arm/Group Title	Pembrolizumab		Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 2 years).		Participants received Investigator's choice of chemotherapy for up to approximately 2 years: paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle.
All Cause Mortality
	Pembrolizumab		Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/62 (67.7%)		55/61 (90.2%)
Serious Adverse Events
	Pembrolizumab		Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/62 (35.5%)		22/59 (37.3%)
Blood and lymphatic system disorders
Bone marrow failure	0/62 (0%)	0	2/59 (3.4%)	2
Febrile neutropenia	0/62 (0%)	0	1/59 (1.7%)	1
Cardiac disorders
Cardiopulmonary failure	1/62 (1.6%)	1	0/59 (0%)	0
Ventricular extrasystoles	1/62 (1.6%)	1	0/59 (0%)	0
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula	1/62 (1.6%)	1	0/59 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	0/62 (0%)	0	1/59 (1.7%)	1
Constipation	1/62 (1.6%)	1	0/59 (0%)	0
Diarrhoea	0/62 (0%)	0	3/59 (5.1%)	3
Dysphagia	1/62 (1.6%)	1	0/59 (0%)	0
Gastrointestinal disorder	0/62 (0%)	0	1/59 (1.7%)	1
Gastrointestinal haemorrhage	0/62 (0%)	0	2/59 (3.4%)	2
Oesophageal fistula	1/62 (1.6%)	1	2/59 (3.4%)	2
Oesophageal obstruction	2/62 (3.2%)	2	1/59 (1.7%)	1
Upper gastrointestinal haemorrhage	0/62 (0%)	0	1/59 (1.7%)	1
Vomiting	1/62 (1.6%)	3	0/59 (0%)	0
General disorders
Chest discomfort	1/62 (1.6%)	1	0/59 (0%)	0
Death	2/62 (3.2%)	2	0/59 (0%)	0
Pyrexia	0/62 (0%)	0	2/59 (3.4%)	2
Hepatobiliary disorders
Autoimmune hepatitis	1/62 (1.6%)	1	0/59 (0%)	0
Liver injury	1/62 (1.6%)	1	0/59 (0%)	0
Immune system disorders
Anaphylactic reaction	0/62 (0%)	0	1/59 (1.7%)	1
Infections and infestations
Lung infection	1/62 (1.6%)	1	0/59 (0%)	0
Lymph gland infection	0/62 (0%)	0	1/59 (1.7%)	1
Oesophageal infection	0/62 (0%)	0	1/59 (1.7%)	1
Pneumonia	2/62 (3.2%)	2	2/59 (3.4%)	2
Respiratory tract infection	1/62 (1.6%)	1	0/59 (0%)	0
Upper respiratory tract infection	2/62 (3.2%)	2	1/59 (1.7%)	1
Injury, poisoning and procedural complications
Anastomotic fistula	1/62 (1.6%)	1	0/59 (0%)	0
Investigations
Alanine aminotransferase increased	1/62 (1.6%)	1	0/59 (0%)	0
Aspartate aminotransferase increased	1/62 (1.6%)	1	0/59 (0%)	0
Neutrophil count decreased	0/62 (0%)	0	1/59 (1.7%)	1
Platelet count decreased	1/62 (1.6%)	1	0/59 (0%)	0
White blood cell count decreased	0/62 (0%)	0	2/59 (3.4%)	2
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/62 (1.6%)	1	0/59 (0%)	0
Electrolyte imbalance	1/62 (1.6%)	1	0/59 (0%)	0
Hyperglycaemia	0/62 (0%)	0	1/59 (1.7%)	1
Hypoalbuminaemia	1/62 (1.6%)	1	0/59 (0%)	0
Hypoglycaemia	0/62 (0%)	0	1/59 (1.7%)	1
Hyponatraemia	1/62 (1.6%)	1	0/59 (0%)	0
Malnutrition	1/62 (1.6%)	1	0/59 (0%)	0
Musculoskeletal and connective tissue disorders
Myositis	1/62 (1.6%)	1	0/59 (0%)	0
Nervous system disorders
Altered state of consciousness	0/62 (0%)	0	1/59 (1.7%)	1
Psychiatric disorders
Suicide attempt	0/62 (0%)	0	2/59 (3.4%)	2
Renal and urinary disorders
Acute kidney injury	1/62 (1.6%)	1	0/59 (0%)	0
Urinary retention	1/62 (1.6%)	1	0/59 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acquired tracheo-oesophageal fistula	1/62 (1.6%)	1	1/59 (1.7%)	1
Haemoptysis	0/62 (0%)	0	2/59 (3.4%)	2
Pneumonitis	1/62 (1.6%)	1	0/59 (0%)	0
Other (Not Including Serious) Adverse Events
	Pembrolizumab		Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	57/62 (91.9%)		55/59 (93.2%)
Blood and lymphatic system disorders
Anaemia	15/62 (24.2%)	20	30/59 (50.8%)	47
Leukopenia	1/62 (1.6%)	2	7/59 (11.9%)	23
Neutropenia	0/62 (0%)	0	5/59 (8.5%)	17
Endocrine disorders
Hypothyroidism	12/62 (19.4%)	15	2/59 (3.4%)	2
Gastrointestinal disorders
Abdominal distension	4/62 (6.5%)	4	1/59 (1.7%)	1
Abdominal pain	3/62 (4.8%)	5	3/59 (5.1%)	3
Abdominal pain upper	5/62 (8.1%)	7	4/59 (6.8%)	4
Constipation	10/62 (16.1%)	13	10/59 (16.9%)	14
Diarrhoea	7/62 (11.3%)	8	17/59 (28.8%)	39
Dysphagia	4/62 (6.5%)	4	3/59 (5.1%)	3
Gastrooesophageal reflux disease	6/62 (9.7%)	8	6/59 (10.2%)	7
Nausea	6/62 (9.7%)	6	16/59 (27.1%)	22
Vomiting	5/62 (8.1%)	8	19/59 (32.2%)	36
General disorders
Asthenia	12/62 (19.4%)	12	4/59 (6.8%)	4
Chest pain	5/62 (8.1%)	6	1/59 (1.7%)	1
Fatigue	3/62 (4.8%)	5	10/59 (16.9%)	10
Malaise	2/62 (3.2%)	2	6/59 (10.2%)	7
Pyrexia	4/62 (6.5%)	6	9/59 (15.3%)	13
Hepatobiliary disorders
Hepatic function abnormal	4/62 (6.5%)	4	2/59 (3.4%)	2
Infections and infestations
Lung infection	4/62 (6.5%)	6	5/59 (8.5%)	5
Pneumonia	5/62 (8.1%)	5	3/59 (5.1%)	3
Upper respiratory tract infection	4/62 (6.5%)	4	2/59 (3.4%)	2
Investigations
Alanine aminotransferase increased	11/62 (17.7%)	12	4/59 (6.8%)	6
Aspartate aminotransferase increased	5/62 (8.1%)	6	5/59 (8.5%)	8
Blood bilirubin increased	4/62 (6.5%)	4	2/59 (3.4%)	3
Blood chloride decreased	0/62 (0%)	0	3/59 (5.1%)	4
Blood glucose increased	1/62 (1.6%)	1	3/59 (5.1%)	3
Blood lactate dehydrogenase increased	2/62 (3.2%)	2	4/59 (6.8%)	4
Blood urea increased	2/62 (3.2%)	3	3/59 (5.1%)	4
Gamma-glutamyltransferase increased	7/62 (11.3%)	7	4/59 (6.8%)	4
Haemoglobin decreased	0/62 (0%)	0	3/59 (5.1%)	3
Lymphocyte count decreased	1/62 (1.6%)	1	8/59 (13.6%)	10
Neutrophil count decreased	2/62 (3.2%)	3	17/59 (28.8%)	54
Neutrophil count increased	1/62 (1.6%)	1	3/59 (5.1%)	3
Platelet count decreased	3/62 (4.8%)	3	5/59 (8.5%)	6
Tri-iodothyronine decreased	1/62 (1.6%)	1	3/59 (5.1%)	3
Weight decreased	12/62 (19.4%)	12	16/59 (27.1%)	18
White blood cell count decreased	4/62 (6.5%)	7	28/59 (47.5%)	79
White blood cell count increased	2/62 (3.2%)	2	3/59 (5.1%)	3
Metabolism and nutrition disorders
Decreased appetite	11/62 (17.7%)	12	11/59 (18.6%)	13
Hypercalcaemia	4/62 (6.5%)	4	1/59 (1.7%)	1
Hyperglycaemia	5/62 (8.1%)	5	3/59 (5.1%)	4
Hypoalbuminaemia	13/62 (21%)	19	11/59 (18.6%)	12
Hypochloraemia	4/62 (6.5%)	6	1/59 (1.7%)	1
Hypokalaemia	5/62 (8.1%)	5	11/59 (18.6%)	14
Hyponatraemia	3/62 (4.8%)	3	4/59 (6.8%)	6
Hypophosphataemia	2/62 (3.2%)	2	3/59 (5.1%)	4
Hypoproteinaemia	3/62 (4.8%)	3	4/59 (6.8%)	6
Musculoskeletal and connective tissue disorders
Back pain	7/62 (11.3%)	7	1/59 (1.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	5/62 (8.1%)	5	3/59 (5.1%)	3
Psychiatric disorders
Insomnia	3/62 (4.8%)	3	4/59 (6.8%)	4
Renal and urinary disorders
Haematuria	2/62 (3.2%)	3	3/59 (5.1%)	3
Proteinuria	6/62 (9.7%)	6	1/59 (1.7%)	2
Respiratory, thoracic and mediastinal disorders
Cough	11/62 (17.7%)	17	7/59 (11.9%)	9
Dysphonia	2/62 (3.2%)	2	3/59 (5.1%)	3
Dyspnoea	6/62 (9.7%)	8	1/59 (1.7%)	1
Hiccups	0/62 (0%)	0	3/59 (5.1%)	3
Productive cough	3/62 (4.8%)	3	7/59 (11.9%)	7
Skin and subcutaneous tissue disorders
Alopecia	0/62 (0%)	0	7/59 (11.9%)	7
Rash	4/62 (6.5%)	5	1/59 (1.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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