Study of Pembrolizumab (MK-3475) Versus Investigator's Choice Standard Therapy for Participants With Advanced Esophageal/Esophagogastric Junction Carcinoma That Progressed After First-Line Therapy (MK-3475-181/KEYNOTE-181)
Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT02564263
Collaborator
(none)
628
2
75.4
Study Details
Study Description
Brief Summary
In this study, participants with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ) that had progressed after first-line standard therapy were randomized to receive either pembrolizumab (MK-3475) OR the Investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan.
The primary study hypothesis was that treatment with pembrolizumab would prolong overall survival (OS) as compared to treatment with standard chemotherapy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
628 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 1, 2015
Actual Primary Completion Date
:
Oct 15, 2018
Actual Study Completion Date
:
Mar 14, 2022
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Pembrolizumab 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 25 months). |
Biological: pembrolizumab
IV infusion
Other Names:
|
| Active Comparator: Chemotherapy Participants received Investigator's choice of 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 19 months). |
Drug: paclitaxel
IV infusion
Other Names:
Drug: docetaxel
IV infusion
Other Names:
Drug: irinotecan
IV infusion
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus [Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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.
- Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10) [Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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.
- Overall Survival (OS) in All Participants [Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)]
OS was defined as the time from randomization to death due to any cause. Median OS in all participants is presented.
Secondary Outcome Measures
- Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants [Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 blinded independent central review per RECIST 1.1 in all participants is presented.
- Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants [Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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. The percentage of all participants who experienced a CR or PR is presented.
- 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 [Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 blinded independent central review per RECIST 1.1 is presented for participants with SCC of the esophagus.
- 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) [Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 blinded independent central review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10.
- 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 [Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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. The percentage of participants with SCC of the esophagus who experienced a CR or PR is presented.
- 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) [Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR is presented.
- Number of Participants Experiencing an Adverse Event (AE) [Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 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.
- Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE) [Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 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 treatment
-
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 treatment
-
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 treatment
-
Known history of human immunodeficiency virus (HIV) infection
-
Known history of or is positive for hepatitis B or known active hepatitis C
-
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 treatment
-
Has ascites or pleural effusion by physical exam
-
Has experienced documented objective radiographic or clinical disease progression during or after receiving >1 line of therapy
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:
NCT02564263
Other Study ID Numbers:
- 3475-181
- 163145
- MK-3475-181
- KEYNOTE-181
- 2015-002782-32
First Posted:
Sep 30, 2015
Last Update Posted:
Jun 1, 2022
Last Verified:
May 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
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | This results disclosure is based on a data cutoff date of 15-Oct-2018, at which time 67 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Period Title: Overall Study | ||
| STARTED | 314 | 314 |
| Treated | 314 | 296 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 314 | 314 |
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 25 months). | Participants received Investigator's choice of 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 19 months). | Total of all reporting groups |
| Overall Participants | 314 | 314 | 628 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
62.6
(9.4)
|
62.0
(9.6)
|
62.3
(9.5)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
41
13.1%
|
43
13.7%
|
84
13.4%
|
| Male |
273
86.9%
|
271
86.3%
|
544
86.6%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
19
6.1%
|
26
8.3%
|
45
7.2%
|
| Not Hispanic or Latino |
288
91.7%
|
274
87.3%
|
562
89.5%
|
| Unknown or Not Reported |
7
2.2%
|
14
4.5%
|
21
3.3%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
1
0.3%
|
1
0.2%
|
| Asian |
126
40.1%
|
122
38.9%
|
248
39.5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
1
0.3%
|
1
0.2%
|
| Black or African American |
3
1%
|
3
1%
|
6
1%
|
| White |
179
57%
|
173
55.1%
|
352
56.1%
|
| More than one race |
2
0.6%
|
4
1.3%
|
6
1%
|
| Unknown or Not Reported |
4
1.3%
|
10
3.2%
|
14
2.2%
|
| Programmed Death-Ligand 1 (PD-L1) Status: Combined Positive Score (CPS) (Count of Participants) | |||
| PD-L1 CPS ≥10 |
107
34.1%
|
115
36.6%
|
222
35.4%
|
| PD-L1 CPS <10 |
201
64%
|
196
62.4%
|
397
63.2%
|
| Not Evaluable |
6
1.9%
|
3
1%
|
9
1.4%
|
| Geographic Region (Count of Participants) | |||
| Asia |
121
38.5%
|
122
38.9%
|
243
38.7%
|
| RoW |
193
61.5%
|
192
61.1%
|
385
61.3%
|
| Tumor Histology (Count of Participants) | |||
| Squamous cell carcinoma |
198
63.1%
|
203
64.6%
|
401
63.9%
|
| Adenocarcinoma of esophagus & EGJ Siewert type I |
116
36.9%
|
111
35.4%
|
227
36.1%
|
Outcome Measures
| 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 | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Measure Participants | 198 | 203 |
| Median (95% Confidence Interval) [Months] |
8.2
|
7.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Chemotherapy |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.00894 |
| Comments | One-sided p-value based on stratified log-rank test | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.77 | |
| Confidence Interval |
(2-Sided) 95% 0.63 to 0.96 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) | |
| 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 | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Measure Participants | 107 | 115 |
| Median (95% Confidence Interval) [Months] |
9.3
|
6.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Chemotherapy |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.00855 |
| Comments | One-sided p-value based on stratified log-rank test | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.70 | |
| Confidence Interval |
(2-Sided) 95% 0.52 to 0.94 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the esophagogastric junction [EGJ]) | |
| 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 | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Measure Participants | 314 | 314 |
| Median (95% Confidence Interval) [Months] |
7.1
|
7.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Chemotherapy |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0531 |
| Comments | One-sided p-value based on stratified maximum weighted log rank test: the maximum of the log-rank test statistic & a weighted log-rank Fleming-Harrington (0,1) test statistic | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.89 | |
| Confidence Interval |
(2-Sided) 95% 0.75 to 1.05 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the esophagogastric junction [EGJ]) | |
| 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 blinded independent central review per RECIST 1.1 in all participants is presented. |
| Time Frame | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Measure Participants | 314 | 314 |
| Median (95% Confidence Interval) [Months] |
2.1
|
3.4
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Chemotherapy |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.287 |
| Comments | One-sided p-value based on stratified maximum weighted log rank test: the maximum of the log-rank test statistic & a weighted log-rank Fleming-Harrington (0,1) test statistic | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.11 | |
| Confidence Interval |
(2-Sided) 95% 0.94 to 1.31 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the EGJ) | |
| 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. The percentage of all participants who experienced a CR or PR is presented. |
| Time Frame | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Measure Participants | 314 | 314 |
| Number (95% Confidence Interval) [Percentage of Participants] |
13.1
4.2%
|
6.7
2.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Chemotherapy |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0037 |
| 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 | 6.4 | |
| Confidence Interval |
(2-Sided) 95% 1.7 to 11.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Miettinen & Nurminen method stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type I adenocarcinoma of the EGJ) | |
| 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 blinded independent central review per RECIST 1.1 is presented for participants with SCC of the esophagus. |
| Time Frame | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Measure Participants | 198 | 203 |
| Median (95% Confidence Interval) [Months] |
2.2
|
3.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Chemotherapy |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.216 |
| Comments | One-sided p-value based on stratified log-rank test | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.92 | |
| Confidence Interval |
(2-Sided) 95% 0.75 to 1.13 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) | |
| 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 blinded independent central review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10. |
| Time Frame | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Measure Participants | 107 | 115 |
| Median (95% Confidence Interval) [Months] |
2.6
|
3.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Chemotherapy |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.015 |
| Comments | One-sided p-value based on stratified log-rank test | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.73 | |
| Confidence Interval |
(2-Sided) 95% 0.54 to 0.97 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox regression model with treatment as a covariate stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type 1 adenocarcinoma of the EGJ) | |
| 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. The percentage of participants with SCC of the esophagus who experienced a CR or PR is presented. |
| Time Frame | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Measure Participants | 198 | 203 |
| Number (95% Confidence Interval) [Percentage of Participants] |
16.7
5.3%
|
7.4
2.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Chemotherapy |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0022 |
| Comments | One-sided p-value for testing. H0: difference in %=0; H1: difference in %>0. | |
| Method | Miettinen & Nurminen method | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | 9.2 | |
| Confidence Interval |
(2-Sided) 95% 3.0 to 15.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Miettinen & Nurminen method stratified by geographic region (Asia vs RoW) | |
| 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. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR is presented. |
| Time Frame | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 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 25 months). | Participants received Investigator's choice of 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 19 months). |
| Measure Participants | 107 | 115 |
| Number (95% Confidence Interval) [Percentage of Participants] |
21.5
6.8%
|
6.1
1.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Chemotherapy |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0006 |
| Comments | One-sided p-value for testing. H0: difference in %=0; H1: difference in %>0. | |
| Method | Miettinen & Nurminen method | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | 15.1 | |
| Confidence Interval |
(2-Sided) 95% 6.2 to 24.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Miettinen & Nurminen method stratified by geographic region (Asia vs RoW) & tumor histology (SCC vs adenocarcinoma/Siewert type I adenocarcinoma of the EGJ) | |
| 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 | Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| 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 | Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months) | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Safety Population: All participants who received ≥1 dose of study treatment. Per protocol, disease progression of cancer under study was not considered an Adverse events (AE) unless considered related to study treatment. Therefore, Medical Dictionary for Regulatory Activities (MedDRA) preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "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 25 months). | Participants received Investigator's choice of 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 19 months). | ||
All Cause Mortality |
||||
| Pembrolizumab | Chemotherapy | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 271/314 (86.3%) | 284/314 (90.4%) | ||
Serious Adverse Events |
||||
| Pembrolizumab | Chemotherapy | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 124/314 (39.5%) | 121/296 (40.9%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 2/314 (0.6%) | 2 | 5/296 (1.7%) | 5 |
| Febrile neutropenia | 1/314 (0.3%) | 1 | 22/296 (7.4%) | 24 |
| Immune thrombocytopenic purpura | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Leukopenia | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Neutropenia | 0/314 (0%) | 0 | 4/296 (1.4%) | 5 |
| Cardiac disorders | ||||
| Acute left ventricular failure | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Acute myocardial infarction | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Atrial fibrillation | 2/314 (0.6%) | 3 | 2/296 (0.7%) | 2 |
| Cardio-respiratory arrest | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Myocarditis | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Sinus tachycardia | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Tachycardia | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Congenital, familial and genetic disorders | ||||
| Tracheo-oesophageal fistula | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Endocrine disorders | ||||
| Hypercalcaemia of malignancy | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Hypophysitis | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Inappropriate antidiuretic hormone secretion | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Eye disorders | ||||
| Cataract | 1/314 (0.3%) | 2 | 0/296 (0%) | 0 |
| Gastrointestinal disorders | ||||
| Abdominal distension | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Abdominal pain | 3/314 (1%) | 3 | 2/296 (0.7%) | 2 |
| Colitis | 3/314 (1%) | 3 | 0/296 (0%) | 0 |
| Constipation | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Diarrhoea | 1/314 (0.3%) | 1 | 5/296 (1.7%) | 5 |
| Diverticulum oesophageal | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Dysphagia | 11/314 (3.5%) | 12 | 1/296 (0.3%) | 1 |
| Enterocolitis | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Gastrointestinal haemorrhage | 2/314 (0.6%) | 2 | 4/296 (1.4%) | 4 |
| Gastrointestinal hypomotility | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Haematemesis | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Impaired gastric emptying | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Intestinal perforation | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Nausea | 1/314 (0.3%) | 1 | 3/296 (1%) | 3 |
| Oesophageal fistula | 2/314 (0.6%) | 2 | 0/296 (0%) | 0 |
| Oesophageal haemorrhage | 4/314 (1.3%) | 4 | 0/296 (0%) | 0 |
| Oesophageal obstruction | 3/314 (1%) | 3 | 1/296 (0.3%) | 1 |
| Oesophageal perforation | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Oesophageal stenosis | 2/314 (0.6%) | 2 | 1/296 (0.3%) | 1 |
| Oesophageal ulcer | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Oesophagitis | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Peritoneal adhesions | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Upper gastrointestinal haemorrhage | 0/314 (0%) | 0 | 3/296 (1%) | 3 |
| Vomiting | 2/314 (0.6%) | 2 | 5/296 (1.7%) | 5 |
| General disorders | ||||
| Asthenia | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Chest pain | 2/314 (0.6%) | 2 | 0/296 (0%) | 0 |
| Death | 5/314 (1.6%) | 5 | 10/296 (3.4%) | 10 |
| Fatigue | 2/314 (0.6%) | 2 | 2/296 (0.7%) | 2 |
| General physical health deterioration | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Pyrexia | 4/314 (1.3%) | 4 | 5/296 (1.7%) | 5 |
| Strangulated hernia | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Hepatobiliary disorders | ||||
| Autoimmune hepatitis | 4/314 (1.3%) | 4 | 0/296 (0%) | 0 |
| Cholecystitis | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Cholecystitis acute | 2/314 (0.6%) | 2 | 0/296 (0%) | 0 |
| Hepatic failure | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Hepatic function abnormal | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Liver injury | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Infections and infestations | ||||
| Appendicitis | 0/314 (0%) | 0 | 2/296 (0.7%) | 2 |
| Bacteraemia | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Bronchitis | 1/314 (0.3%) | 1 | 2/296 (0.7%) | 2 |
| Candida infection | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Cellulitis | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Clostridium difficile colitis | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Device related infection | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Device related sepsis | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Empyema | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Hepatic infection | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Herpes zoster | 1/314 (0.3%) | 1 | 2/296 (0.7%) | 2 |
| Infection | 0/314 (0%) | 0 | 2/296 (0.7%) | 2 |
| Liver abscess | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Lower respiratory tract infection viral | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Lung infection | 0/314 (0%) | 0 | 2/296 (0.7%) | 2 |
| Mediastinitis | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Peritonitis | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Pneumonia | 14/314 (4.5%) | 15 | 20/296 (6.8%) | 24 |
| Pneumonia bacterial | 0/314 (0%) | 0 | 2/296 (0.7%) | 2 |
| Pneumonia necrotising | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Pulmonary sepsis | 2/314 (0.6%) | 2 | 0/296 (0%) | 0 |
| Respiratory tract infection | 3/314 (1%) | 3 | 2/296 (0.7%) | 2 |
| Sepsis | 3/314 (1%) | 3 | 3/296 (1%) | 4 |
| Septic shock | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Stoma site infection | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Subcutaneous abscess | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Tracheitis | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Tracheostomy infection | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Upper respiratory tract infection | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Urinary tract infection | 2/314 (0.6%) | 2 | 1/296 (0.3%) | 1 |
| Varicella zoster virus infection | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||
| Anastomotic fistula | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Anastomotic leak | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Fall | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Femoral neck fracture | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Foreign body in gastrointestinal tract | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Gastrostomy failure | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Infusion related reaction | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Radiation pneumonitis | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Spinal compression fracture | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Subdural haematoma | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Tracheal injury | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Tracheal obstruction | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Upper limb fracture | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Investigations | ||||
| Hepatic enzyme increased | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Liver function test increased | 1/314 (0.3%) | 2 | 0/296 (0%) | 0 |
| Neutrophil count decreased | 1/314 (0.3%) | 1 | 3/296 (1%) | 3 |
| Weight decreased | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| White blood cell count decreased | 1/314 (0.3%) | 1 | 2/296 (0.7%) | 2 |
| White blood cell count increased | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 2/314 (0.6%) | 2 | 2/296 (0.7%) | 2 |
| Dehydration | 2/314 (0.6%) | 2 | 4/296 (1.4%) | 4 |
| Electrolyte imbalance | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Hypercalcaemia | 3/314 (1%) | 3 | 0/296 (0%) | 0 |
| Hyperglycaemia | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Hypoglycaemia | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Hypokalaemia | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Hyponatraemia | 0/314 (0%) | 0 | 2/296 (0.7%) | 2 |
| Hypophosphataemia | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Type 1 diabetes mellitus | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Back pain | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Fistula inflammation | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Neck pain | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Polymyositis | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Breast cancer | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Cancer pain | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Head and neck cancer | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Metastases to bone | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Nervous system disorders | ||||
| Cerebellar stroke | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Cerebral infarction | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Cerebrovascular accident | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Demyelination | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Dyskinesia | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Dystonia | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Facial paralysis | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Guillain-Barre syndrome | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Haemorrhage intracranial | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Haemorrhagic stroke | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Headache | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Hemiparesis | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Neuralgia | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Neuropathy peripheral | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Radiculopathy | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Spinal cord compression | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Vocal cord paralysis | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Product Issues | ||||
| Device dislocation | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Device occlusion | 2/314 (0.6%) | 2 | 0/296 (0%) | 0 |
| Psychiatric disorders | ||||
| Completed suicide | 2/314 (0.6%) | 2 | 0/296 (0%) | 0 |
| Confusional state | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Delirium | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Renal and urinary disorders | ||||
| Acute kidney injury | 2/314 (0.6%) | 2 | 1/296 (0.3%) | 1 |
| Chronic kidney disease | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Acute respiratory distress syndrome | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Acute respiratory failure | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Aspiration | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Chronic obstructive pulmonary disease | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Dyspnoea | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Haemoptysis | 2/314 (0.6%) | 2 | 0/296 (0%) | 0 |
| Hiccups | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Interstitial lung disease | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Lung disorder | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Pleural effusion | 1/314 (0.3%) | 2 | 2/296 (0.7%) | 2 |
| Pneumonia aspiration | 11/314 (3.5%) | 12 | 5/296 (1.7%) | 5 |
| Pneumonitis | 7/314 (2.2%) | 7 | 0/296 (0%) | 0 |
| Pneumothorax | 1/314 (0.3%) | 1 | 1/296 (0.3%) | 1 |
| Pulmonary embolism | 3/314 (1%) | 3 | 0/296 (0%) | 0 |
| Pulmonary necrosis | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Respiratory failure | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Stridor | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Tracheal fistula | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Upper airway obstruction | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Skin and subcutaneous tissue disorders | ||||
| Dermal cyst | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Vascular disorders | ||||
| Deep vein thrombosis | 1/314 (0.3%) | 1 | 0/296 (0%) | 0 |
| Haemorrhage | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
| Shock haemorrhagic | 0/314 (0%) | 0 | 1/296 (0.3%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Pembrolizumab | Chemotherapy | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 280/314 (89.2%) | 281/296 (94.9%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 52/314 (16.6%) | 60 | 83/296 (28%) | 110 |
| Neutropenia | 0/314 (0%) | 0 | 36/296 (12.2%) | 65 |
| Endocrine disorders | ||||
| Hypothyroidism | 36/314 (11.5%) | 38 | 7/296 (2.4%) | 7 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 34/314 (10.8%) | 35 | 27/296 (9.1%) | 32 |
| Abdominal pain upper | 14/314 (4.5%) | 16 | 17/296 (5.7%) | 19 |
| Constipation | 56/314 (17.8%) | 63 | 55/296 (18.6%) | 62 |
| Diarrhoea | 38/314 (12.1%) | 65 | 79/296 (26.7%) | 120 |
| Dysphagia | 40/314 (12.7%) | 44 | 27/296 (9.1%) | 28 |
| Nausea | 59/314 (18.8%) | 66 | 82/296 (27.7%) | 109 |
| Stomatitis | 9/314 (2.9%) | 9 | 28/296 (9.5%) | 30 |
| Vomiting | 37/314 (11.8%) | 45 | 53/296 (17.9%) | 74 |
| General disorders | ||||
| Asthenia | 45/314 (14.3%) | 48 | 43/296 (14.5%) | 58 |
| Fatigue | 69/314 (22%) | 72 | 87/296 (29.4%) | 121 |
| Malaise | 15/314 (4.8%) | 18 | 19/296 (6.4%) | 26 |
| Oedema peripheral | 19/314 (6.1%) | 20 | 19/296 (6.4%) | 19 |
| Pyrexia | 31/314 (9.9%) | 41 | 45/296 (15.2%) | 58 |
| Investigations | ||||
| Alanine aminotransferase increased | 22/314 (7%) | 26 | 9/296 (3%) | 15 |
| Aspartate aminotransferase increased | 26/314 (8.3%) | 33 | 14/296 (4.7%) | 16 |
| Neutrophil count decreased | 2/314 (0.6%) | 2 | 50/296 (16.9%) | 113 |
| Weight decreased | 39/314 (12.4%) | 39 | 34/296 (11.5%) | 43 |
| White blood cell count decreased | 1/314 (0.3%) | 1 | 52/296 (17.6%) | 114 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 76/314 (24.2%) | 82 | 75/296 (25.3%) | 96 |
| Hyperglycaemia | 17/314 (5.4%) | 22 | 14/296 (4.7%) | 14 |
| Hypoalbuminaemia | 17/314 (5.4%) | 23 | 15/296 (5.1%) | 16 |
| Hypokalaemia | 15/314 (4.8%) | 15 | 28/296 (9.5%) | 39 |
| Hyponatraemia | 19/314 (6.1%) | 27 | 17/296 (5.7%) | 24 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 19/314 (6.1%) | 21 | 16/296 (5.4%) | 18 |
| Back pain | 37/314 (11.8%) | 39 | 24/296 (8.1%) | 27 |
| Myalgia | 8/314 (2.5%) | 10 | 25/296 (8.4%) | 31 |
| Nervous system disorders | ||||
| Dysgeusia | 6/314 (1.9%) | 6 | 17/296 (5.7%) | 17 |
| Neuropathy peripheral | 6/314 (1.9%) | 7 | 25/296 (8.4%) | 28 |
| Peripheral sensory neuropathy | 3/314 (1%) | 3 | 52/296 (17.6%) | 53 |
| Psychiatric disorders | ||||
| Insomnia | 25/314 (8%) | 25 | 16/296 (5.4%) | 42 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 40/314 (12.7%) | 46 | 30/296 (10.1%) | 33 |
| Dyspnoea | 31/314 (9.9%) | 36 | 16/296 (5.4%) | 20 |
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 4/314 (1.3%) | 4 | 88/296 (29.7%) | 88 |
| Pruritus | 23/314 (7.3%) | 27 | 8/296 (2.7%) | 8 |
| Rash | 20/314 (6.4%) | 23 | 25/296 (8.4%) | 27 |
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.
Results Point of Contact
| Name/Title | Senior Vice President, Global Clinical Development |
|---|---|
| Organization | Merck Sharp & Dohme LLC |
| Phone | 1-800-672-6372 |
| ClinicalTrialsDisclosure@merck.com |
Responsible Party:
Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier:
NCT02564263
Other Study ID Numbers:
- 3475-181
- 163145
- MK-3475-181
- KEYNOTE-181
- 2015-002782-32
First Posted:
Sep 30, 2015
Last Update Posted:
Jun 1, 2022
Last Verified:
May 1, 2022