Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial of Pembrolizumab (MK-3475) in Combination with Cisplatin and 5-Fluorouracil versus Placebo in Combination with Cisplatin and 5-Fluorouracil as First-Line Treatment in Subjects with Advanced/Metastatic Esophageal Carcinoma (KEYNOTE-590)
Summary
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EudraCT number |
2017-000958-19 |
Trial protocol |
DE GB ES FR DK RO |
Global end of trial date |
10 Jul 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Jun 2024
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First version publication date |
19 Jun 2024
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
3475-590
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03189719 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
MK-3475-590: Merck | ||
Sponsors
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Sponsor organisation name |
Merck Sharp & Dohme LLC
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Sponsor organisation address |
126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
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Public contact |
Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
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Scientific contact |
Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Jul 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Jul 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Jul 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The purpose of this trial is to evaluate efficacy and safety of pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin and 5-fluorouracil (5-FU) versus placebo plus SOC chemotherapy with cisplatin and 5-FU as first-line treatment in participants with locally advanced or metastatic esophageal carcinoma.
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Jul 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Argentina: 13
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Country: Number of subjects enrolled |
Australia: 20
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Country: Number of subjects enrolled |
Brazil: 29
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Country: Number of subjects enrolled |
Canada: 32
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Country: Number of subjects enrolled |
Chile: 16
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Country: Number of subjects enrolled |
China: 106
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Country: Number of subjects enrolled |
Colombia: 1
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Country: Number of subjects enrolled |
Costa Rica: 7
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Country: Number of subjects enrolled |
Germany: 19
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Country: Number of subjects enrolled |
Denmark: 7
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Country: Number of subjects enrolled |
Spain: 22
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Country: Number of subjects enrolled |
France: 30
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Country: Number of subjects enrolled |
United Kingdom: 22
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Country: Number of subjects enrolled |
Guatemala: 20
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Country: Number of subjects enrolled |
Hong Kong: 15
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Country: Number of subjects enrolled |
Japan: 141
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Country: Number of subjects enrolled |
Korea, Republic of: 59
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Country: Number of subjects enrolled |
Malaysia: 9
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Country: Number of subjects enrolled |
Peru: 9
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Country: Number of subjects enrolled |
Romania: 14
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Country: Number of subjects enrolled |
Russian Federation: 23
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Country: Number of subjects enrolled |
Thailand: 20
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Country: Number of subjects enrolled |
Türkiye: 25
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Country: Number of subjects enrolled |
Taiwan: 43
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Country: Number of subjects enrolled |
United States: 40
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Country: Number of subjects enrolled |
South Africa: 7
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Worldwide total number of subjects |
749
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EEA total number of subjects |
92
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
427
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From 65 to 84 years |
319
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85 years and over |
3
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
749 participants were randomized 1:1 to receive either pembrolizumab plus standard of care (SOC) chemotherapy, or placebo plus SOC chemotherapy. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pembrolizumab + SOC | |||||||||||||||||||||||||||
Arm description |
Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-fluorouracil (5-FU) 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Pembrolizumab
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Investigational medicinal product code |
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Other name |
KEYTRUDA®
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
200 mg administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.
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Investigational medicinal product name |
5-FU
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
800 mg/m^2/day (4000 mg/m^2 total per cycle) administered as continuous IV infusion on Days 1 to 5 (120 hours) of each 3-week cycle, or per local standard for 5-FU administration, up to 35 administrations.
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Investigational medicinal product name |
Cisplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
80 mg/m^2 administered IV Q3W on Day 1 of each 3-week cycle. Duration of cisplatin treatment will be capped at 6 doses.
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Arm title
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Placebo + SOC | |||||||||||||||||||||||||||
Arm description |
Participants received placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle. | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Placebo to pembrolizumab (saline) administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.
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Investigational medicinal product name |
5-FU
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
800 mg/m^2/day (4000 mg/m^2 total per cycle) administered as continuous IV infusion on Days 1 to 5 (120 hours) of each 3-week cycle, or per local standard for 5-FU administration, up to 35 administrations.
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Investigational medicinal product name |
Cisplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
80 mg/m^2 administered IV Q3W on Day 1 of each 3-week cycle. Duration of cisplatin treatment will be capped at 6 doses.
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Baseline characteristics reporting groups
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Reporting group title |
Pembrolizumab + SOC
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Reporting group description |
Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-fluorouracil (5-FU) 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo + SOC
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Reporting group description |
Participants received placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pembrolizumab + SOC
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Reporting group description |
Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-fluorouracil (5-FU) 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle. | ||
Reporting group title |
Placebo + SOC
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Reporting group description |
Participants received placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle. |
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End point title |
OS in Participants With ESCC | ||||||||||||
End point description |
Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the ITT population (all randomized) who had ESCC.
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End point type |
Primary
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End point timeframe |
Up to approximately 34 months
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Statistical analysis title |
OS in ESCC | ||||||||||||
Statistical analysis description |
OS in ESCC participants of the pembrolizumab + SOC arm was compared to OS in ESCC participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
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Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
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Number of subjects included in analysis |
548
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.0006 | ||||||||||||
Method |
Stratified Log-Rank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.72
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.6 | ||||||||||||
upper limit |
0.88 |
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End point title |
Overall Survival (OS) in Participants With Esophageal Squamous Cell Carcinoma (ESCC) Whose Tumors Are Programmed Cell Death-Ligand 1 (PD-L1) Biomarker-Positive (Combined Positive Score [CPS] ≥10) | ||||||||||||
End point description |
Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the Intent-To-Treat (ITT) population (all randomized) who had ESCC and who were PD-L1 CPS ≥10.
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End point type |
Primary
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End point timeframe |
Up to approximately 34 months
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Statistical analysis title |
OS in ESCC PD-L1 CPS ≥10 | ||||||||||||
Statistical analysis description |
OS in ESCC PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to OS in ESCC PD-L1 CPS ≥10 participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
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Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
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Number of subjects included in analysis |
286
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-Rank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.57
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Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.43 | ||||||||||||
upper limit |
0.75 |
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End point title |
OS in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) | ||||||||||||
End point description |
Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the ITT population (all randomized) who were PD-L1 CPS ≥10.
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End point type |
Primary
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End point timeframe |
Up to approximately 34 months
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Statistical analysis title |
OS in PD-L1 CPS ≥10 | ||||||||||||
Statistical analysis description |
OS in PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to OS in PD-L1 CPS ≥10 participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
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Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
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Number of subjects included in analysis |
383
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Analysis specification |
Pre-specified
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Analysis type |
|||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-Rank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.62
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Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.49 | ||||||||||||
upper limit |
0.78 |
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End point title |
OS in All Participants | ||||||||||||
End point description |
Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the ITT population (all randomized).
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End point type |
Primary
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End point timeframe |
Up to approximately 34 months
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Statistical analysis title |
OS in all participants | ||||||||||||
Statistical analysis description |
OS in all participants of the pembrolizumab + SOC arm was compared to OS in all participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World), tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma), and ECOG performance status (0 versus 1).
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Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
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Number of subjects included in analysis |
749
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Analysis specification |
Pre-specified
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Analysis type |
|||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-Rank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.73
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||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.62 | ||||||||||||
upper limit |
0.86 |
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End point title |
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) As Assessed By Investigator in Participants With ESCC | ||||||||||||
End point description |
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, 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 had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized) who had ESCC.
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End point type |
Primary
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End point timeframe |
Up to approximately 34 months
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|
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Statistical analysis title |
PFS in ESCC | ||||||||||||
Statistical analysis description |
PFS in ESCC participants of the pembrolizumab + SOC arm was compared to PFS in ESCC participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
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Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
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Number of subjects included in analysis |
548
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||||||||||||
Analysis specification |
Pre-specified
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||||||||||||
Analysis type |
|||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-Rank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.65
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||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
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||||||||||||
lower limit |
0.54 | ||||||||||||
upper limit |
0.78 |
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End point title |
PFS Per RECIST 1.1 As Assessed By Investigator in All Participants | ||||||||||||
End point description |
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, 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 had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized).
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End point type |
Primary
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||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
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Statistical analysis title |
PFS in all participants | ||||||||||||
Statistical analysis description |
PFS in all participants of the pembrolizumab + SOC arm was compared to PFS in all participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World), tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma), and ECOG performance status (0 versus 1).
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Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
749
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Analysis specification |
Pre-specified
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Analysis type |
|||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-Rank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.65
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.55 | ||||||||||||
upper limit |
0.76 |
|
|||||||||||||
End point title |
PFS Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) | ||||||||||||
End point description |
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, 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 had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized) who were PD-L1 CPS ≥10.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
PFS in PD-L1 CPS ≥10 | ||||||||||||
Statistical analysis description |
PFS in PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to PFS in PD-L1 CPS ≥10 participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
|
||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
383
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Stratified Log-Rank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.51
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.41 | ||||||||||||
upper limit |
0.65 |
|
|||||||||||||
End point title |
ORR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10) | ||||||||||||
End point description |
ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. as assessed by the investigator. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for all participants of the ITT population (all randomized) who had ESCC and who were PD-L1 CPS ≥10.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ORR in ESCC PD-L1 CPS ≥10 | ||||||||||||
Statistical analysis description |
ORR in ESCC PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to ORR in ESCC PD-L1 CPS ≥10 participants of the placebo + SOC arm based on the Miettinen & Nurminen method stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
286
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
One-sided p-value | ||||||||||||
Parameter type |
Difference in Percentage | ||||||||||||
Point estimate |
22.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
11.6 | ||||||||||||
upper limit |
33.4 |
|
|||||||||||||
End point title |
Objective Response Rate (ORR) Per RECIST 1.1 As Assessed By Investigator in All Participants | ||||||||||||
End point description |
ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. as assessed by the investigator. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for all participants of the ITT population (all randomized).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ORR in all participants | ||||||||||||
Statistical analysis description |
ORR in all participants of the pembrolizumab + SOC arm was compared to ORR in all participants of the placebo + SOC arm based on the Miettinen & Nurminen method stratified by geographic region (Asia versus Rest of the World), tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma), and ECOG performance status (0 versus 1).
|
||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
749
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
One-sided p-value | ||||||||||||
Parameter type |
Difference in Percentage | ||||||||||||
Point estimate |
15.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
9 | ||||||||||||
upper limit |
22.5 |
|
|||||||||||||
End point title |
ORR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC | ||||||||||||
End point description |
ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. as assessed by the investigator. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for all participants of the ITT population (all randomized) who had ESCC.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ORR in ESCC | ||||||||||||
Statistical analysis description |
ORR in ESCC participants of the pembrolizumab + SOC arm was compared to ORR in ESCC participants of the placebo + SOC arm based on the Miettinen & Nurminen method stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
548
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.0009 | ||||||||||||
Method |
One-sided p-value | ||||||||||||
Parameter type |
Difference in Percentage | ||||||||||||
Point estimate |
12.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
4.7 | ||||||||||||
upper limit |
20.7 |
|
|||||||||||||
End point title |
Duration of Response (DOR) per RECIST 1.1 As Assessed By Investigator in All Participants | ||||||||||||
End point description |
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, DOR is reported here for all participants of the ITT population (all randomized) who had CR or PR.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
ORR per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10) | ||||||||||||
End point description |
ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. as assessed by the investigator. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for all participants of the ITT population (all randomized) who were PD-L1 CPS ≥10.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ORR in PD-L1 CPS ≥10 | ||||||||||||
Statistical analysis description |
ORR in PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to ORR in PD-L1 CPS ≥10 participants of the placebo + SOC arm based on the Miettinen & Nurminen method stratified by geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
|
||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
383
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
One-sided p-value | ||||||||||||
Parameter type |
Difference in Percentage | ||||||||||||
Point estimate |
24
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
14.3 | ||||||||||||
upper limit |
33.2 |
|
|||||||||||||
End point title |
DOR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10) | ||||||||||||
End point description |
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, DOR is reported here for all participants of the ITT population (all randomized) who had CR or PR, and who had ESCC and were PD-L1 CPS ≥10.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
DOR per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10) | ||||||||||||
End point description |
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, DOR is reported here for all participants of the ITT population (all randomized) who had CR or PR, and were PD-L1 CPS ≥10.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
DOR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC | ||||||||||||
End point description |
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, DOR is reported here for all participants of the ITT population (all randomized) who had CR or PR, and who had ESCC.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 34 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Participants with an Adverse Event (AE) | |||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The number of participants that experienced at least one AE was reported for each treatment arm. All randomized participants who received at least one dose of study treatment were analyzed.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 28 months
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Participants Discontinuing Study Treatment Due to an AE | |||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The number of participants that discontinued any study drug due to an AE was reported for each treatment arm. All randomized participants who received at least one dose of study treatment were analyzed.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to approximately 27 months
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from Baseline To Week 18 in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Combined Score in All Participants | ||||||||||||
End point description |
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was reported by treatment arm as a pre-specified secondary analysis for all participants. All randomized participants who received at least one dose of study treatment and completed at least 1 EORTC-QLQ-C30 assessment were analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 18
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
EORTC-QLQ-C30 GHS/QoL combined score | ||||||||||||
Statistical analysis description |
Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between treatment arms based on a constrained longitudinal data analysis (cLDA) model with the EORTC-QLQ-C30 GHS/QoL scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0 versus 1).
|
||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
729
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.953 | ||||||||||||
Method |
constrained Longitudinal Data Analysis | ||||||||||||
Parameter type |
Difference in LS Means | ||||||||||||
Point estimate |
-0.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.4 | ||||||||||||
upper limit |
3.2 |
|
|||||||||||||
End point title |
Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10) | ||||||||||||
End point description |
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was reported by treatment arm as a pre-specified secondary analysis for all participants who had ESCC and who were PD-L1 CPS ≥10. All randomized participants who received at least one dose of study treatment, completed at least 1 EORTC-QLQ-C30 assessment, who had ESCC, and who were PD-L1 CPS ≥10 were analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 18
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
EORTC-QLQ-C30 GHS/QoL combined score | ||||||||||||
Statistical analysis description |
Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between treatment arms based on a cLDA model with the EORTC-QLQ-C30 GHS/QoL scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
280
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.5053 | ||||||||||||
Method |
constrained Longitudinal Data Analysis | ||||||||||||
Parameter type |
Difference in LS Means | ||||||||||||
Point estimate |
-1.95
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-7.72 | ||||||||||||
upper limit |
3.82 |
|
|||||||||||||
End point title |
Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC | ||||||||||||
End point description |
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was reported by treatment arm as a pre-specified secondary analysis for all participants who had ESCC. All randomized participants who received at least one dose of study treatment, completed at least 1 EORTC-QLQ-C30 assessment, and who had ESCC were analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 18
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
EORTC-QLQ-C30 GHS/QoL combined score | ||||||||||||
Statistical analysis description |
Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between treatment arms based on a cLDA model with the EORTC-QLQ-C30 GHS/QoL scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
534
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.9742 | ||||||||||||
Method |
constrained Longitudinal Data Analysis | ||||||||||||
Parameter type |
Difference in LS Means | ||||||||||||
Point estimate |
-0.06
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.93 | ||||||||||||
upper limit |
3.81 |
|
||||||||||||||||||||||
End point title |
Change from Baseline in the EORTC Quality Of Life Questionnaire Oesophageal Module (QLQ-OES18) Subscale Scores in All Participants | |||||||||||||||||||||
End point description |
The EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (3 items), Pain subscale (3 items), and Reflux subscale (2 items) were evaluated. All subscale items were scored using a four-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores represent a higher ("worse") level of symptoms. Per protocol, change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for all randomized participants who received at least one dose of study treatment and completed at least 1 EORTC QLQ-OES18 assessment.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 18
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
DYSPHAGIA: Change from baseline to Week 18 in EORTC QLQ-OES18 Dysphagia subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0 versus 1).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
725
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.0436 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-5.54
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-10.93 | |||||||||||||||||||||
upper limit |
-0.16 | |||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
REFLUX: Change from baseline to Week 18 in EORTC QLQ-OES18 Reflux subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0 versus 1).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
725
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.5932 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-0.93
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-4.36 | |||||||||||||||||||||
upper limit |
2.49 | |||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
PAIN: Change from baseline to Week 18 in EORTC QLQ-OES18 Pain subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0 versus 1).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
725
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.0487 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-2.94
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-5.86 | |||||||||||||||||||||
upper limit |
-0.02 |
|
|||||||||||||
End point title |
Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10) | ||||||||||||
End point description |
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was reported by treatment arm as a pre-specified secondary analysis for all participants who were PD-L1 CPS ≥10. All randomized participants who received at least one dose of study treatment, completed at least 1 EORTC-QLQ-C30 assessment, and who were PD-L1 CPS ≥10 were analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 18
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
EORTC-QLQ-C30 GHS/QoL combined score | ||||||||||||
Statistical analysis description |
Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between treatment arms based on a cLDA model with the EORTC-QLQ-C30 GHS/QoL scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
|
||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
||||||||||||
Number of subjects included in analysis |
375
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
|||||||||||||
P-value |
= 0.481 | ||||||||||||
Method |
constrained Longitudinal Data Analysis | ||||||||||||
Parameter type |
Difference in LS Means | ||||||||||||
Point estimate |
-1.77
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-6.71 | ||||||||||||
upper limit |
3.17 |
|
||||||||||||||||||||||
End point title |
Change from Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10) | |||||||||||||||||||||
End point description |
EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer containing 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (3 items), Pain subscale (3 items), and Reflux subscale (2 items) were evaluated. All subscale items scored using a 4-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for subscales were standardized into a range of 0-100 by linear transformation, with higher symptom scores representing a higher ("worse") level of symptoms. Change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales reported for all randomized participants with ESCC and PD-L1 CPS≥10 in each treatment arm who received ≥1 dose of study treatment and completed at least 1 EORTC QLQ-OES18 assessment.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 18
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
DYSPHAGIA: Change from baseline to Week 18 in EORTC QLQ-OES18 Dysphagia subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
277
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.0564 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-8.68
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-17.59 | |||||||||||||||||||||
upper limit |
0.24 | |||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
REFLUX: Change from baseline to Week 18 in EORTC QLQ-OES18 Reflux subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
277
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.0816 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-5.11
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-10.86 | |||||||||||||||||||||
upper limit |
0.65 | |||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
PAIN: Change from baseline to Week 18 in EORTC QLQ-OES18 Pain subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
277
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.3813 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-2.13
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-6.93 | |||||||||||||||||||||
upper limit |
2.66 |
|
||||||||||||||||||||||
End point title |
Change from Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC | |||||||||||||||||||||
End point description |
EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (3 items), Pain subscale (3 items), and Reflux subscale (2 items) were evaluated. All subscale items were scored using a four-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores representing a higher ("worse") level of symptoms. Change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for all randomized participants with ESCC in each treatment arm who received ≥1 dose of study treatment and completed ≥1 EORTC QLQ-OES18 assessment.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 18
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
DYSPHAGIA: Change from baseline to Week 18 in EORTC QLQ-OES18 Dysphagia subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
531
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.1632 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-4.49
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-10.81 | |||||||||||||||||||||
upper limit |
1.83 | |||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
REFLUX: Change from baseline to Week 18 in EORTC QLQ-OES18 Reflux subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
531
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.4598 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-1.5
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-5.47 | |||||||||||||||||||||
upper limit |
2.48 | |||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
PAIN: Change from baseline to Week 18 in EORTC QLQ-OES18 Pain subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
531
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.3259 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-1.71
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-5.12 | |||||||||||||||||||||
upper limit |
1.71 |
|
||||||||||||||||||||||
End point title |
Change from Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10) | |||||||||||||||||||||
End point description |
EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (3 items), Pain subscale (3 items), and Reflux subscale (2 items) were evaluated. All subscale items were scored using a 4-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores representing a higher ("worse") level of symptoms. Change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for all randomized PD-L1 CPS≥10 participants in each treatment arm who received ≥1 dose of study treatment and completed ≥1 EORTC QLQ-OES18 assessment.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 18
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
DYSPHAGIA: Change from baseline to Week 18 in EORTC QLQ-OES18 Dysphagia subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
371
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.0317 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-8.2
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-15.67 | |||||||||||||||||||||
upper limit |
-0.73 | |||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
REFLUX: Change from baseline to Week 18 in EORTC QLQ-OES18 Reflux subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
371
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.0555 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-4.76
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-9.64 | |||||||||||||||||||||
upper limit |
0.11 | |||||||||||||||||||||
Statistical analysis title |
EORTC QLQ-OES18- Dysphagia + Pain + Reflux | |||||||||||||||||||||
Statistical analysis description |
PAIN: Change from baseline to Week 18 in EORTC QLQ-OES18 Pain subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
|
|||||||||||||||||||||
Comparison groups |
Pembrolizumab + SOC v Placebo + SOC
|
|||||||||||||||||||||
Number of subjects included in analysis |
371
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
||||||||||||||||||||||
P-value |
= 0.0945 | |||||||||||||||||||||
Method |
constrained Longitudinal Data Analysis | |||||||||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||||||||
Point estimate |
-3.57
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-7.77 | |||||||||||||||||||||
upper limit |
0.62 |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
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Timeframe for reporting adverse events |
Up to approximately 70 months
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Adverse event reporting additional description |
Serious and Non serious AE tables include all treated participants. Per protocol, disease progression of cancer on study was not considered an AE unless considered related to study drug. Thus, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug were excluded as AEs.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.0
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Reporting groups
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Reporting group title |
Placebo + SOC
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Reporting group description |
Participants received placebo to pembrolizumab (saline) IV Q3W along with SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pembrolizumab + SOC
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Reporting group description |
Participants received pembrolizumab 200 mg IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Jan 2018 |
The major change of Amendment 2 (AM 2) was a change in the primary biomarker from GEP to PD-L1; clarification of the 5-FU dosing; an update to the Statistical Analysis Plan; and a reduction in PK/ADA sampling. |
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21 Dec 2018 |
The major change of AM 5 was to extend the enrollment period beyond the Global Cohort to achieve the required sample size of the China Cohort to investigate efficacy and safety in Chinese participants. |
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10 Feb 2020 |
Major changes of AM 8 included addition of 3 primary objectives and corresponding hypotheses (OS in ESCC participants, OS in ESCC participants with PD-L1 CPS ≥10, and PFS in ESCC participants), update of secondary objectives (ORR and DOR endpoints in the ESCC and ESCC PD-L1 CPS ≥10 populations) and exploratory objectives (PFS per immune related RECIST in the ESCC and ESCC PD-L1 CPS ≥10 populations), merging of the Global Cohort and the China Extension Study Cohort into the Global Study group, and inclusion of assessment of DOR, QoL (C30) and QoL (OES18) in all prespecified populations. |
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14 Jul 2020 |
Major changes of AM 9 included a change in the primary PFS endpoint from BICR-assessed to investigator-assessed, and elimination of one of the two planned efficacy interim analyses. |
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01 Jul 2021 |
The major change of AM 10 was to update the dose modification and toxicity management guidelines for immune-related AEs. |
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28 Nov 2022 |
The major change of AM 11 was to update the name of the Sponsor from “Merck Sharp & Dohme Corp.” to “Merck Sharp & Dohme LLC”. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |