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A Study of Pembrolizumab (MK-3475) for First Line Treatment of Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck (MK-3475-048/KEYNOTE-048)

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ClinicalTrials.gov Identifier: NCT02358031
Recruitment Status : Active, not recruiting
First Posted : February 6, 2015
Results First Posted : February 17, 2020
Last Update Posted : October 23, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Recurrent Head and Neck Cancer
Metastatic Head and Neck Cancer
Interventions Biological: Pembrolizumab
Drug: Cisplatin
Drug: Carboplatin
Drug: 5-FU
Biological: Cetuximab
Enrollment 882
Recruitment Details Participants with first line recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) were recruited to examine the efficacy and safety of pembrolizumab monotherapy (pembro mono) versus pembrolizumab plus chemotherapy (pembro combo) versus cetuximab plus chemotherapy (control).
Pre-assignment Details Of 1228 participants screened, 882 were randomized to the pembro mono arm, pembro combo arm, or control arm. 22 participants in the control arm that enrolled during an enrollment pause of the pembro combo arm were excluded from efficacy comparisons between the pembro combo arm and control arm.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months. Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum). Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Period Title: Overall Study
Started 301 281 300
Treated 300 276 287
Pembro Mono v Control Efficacy Analyses 301 0 300
Pembro Combo v Control Efficacy Analyses 0 281 278
Completed 0 0 0
Not Completed 301 281 300
Reason Not Completed
Death             226             204             249
Lost to Follow-up             0             1             1
Withdrawal by Subject             14             12             17
Ongoing in Study             61             64             33
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control) Total
Hide Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months. Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum). Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum). Total of all reporting groups
Overall Number of Baseline Participants 301 281 300 882
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 301 participants 281 participants 300 participants 882 participants
61.2  (9.4) 60.7  (9.8) 61.0  (10.0) 61.0  (9.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 301 participants 281 participants 300 participants 882 participants
Female
51
  16.9%
57
  20.3%
39
  13.0%
147
  16.7%
Male
250
  83.1%
224
  79.7%
261
  87.0%
735
  83.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 301 participants 281 participants 300 participants 882 participants
Hispanic or Latino
46
  15.3%
45
  16.0%
44
  14.7%
135
  15.3%
Not Hispanic or Latino
233
  77.4%
213
  75.8%
231
  77.0%
677
  76.8%
Unknown or Not Reported
22
   7.3%
23
   8.2%
25
   8.3%
70
   7.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 301 participants 281 participants 300 participants 882 participants
American Indian or Alaska Native
5
   1.7%
3
   1.1%
6
   2.0%
14
   1.6%
Asian
58
  19.3%
60
  21.4%
54
  18.0%
172
  19.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
4
   1.3%
11
   3.9%
6
   2.0%
21
   2.4%
White
219
  72.8%
203
  72.2%
224
  74.7%
646
  73.2%
More than one race
12
   4.0%
4
   1.4%
9
   3.0%
25
   2.8%
Unknown or Not Reported
3
   1.0%
0
   0.0%
1
   0.3%
4
   0.5%
Eastern Cooperative Group (ECOG) Performance Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 301 participants 281 participants 300 participants 882 participants
ECOG = 0
118
  39.2%
110
  39.1%
117
  39.0%
345
  39.1%
ECOG = 1
183
  60.8%
171
  60.9%
183
  61.0%
537
  60.9%
[1]
Measure Description: An ECOG Performance Status of 0 (Fully active, able to carry on all pre-disease performance without restriction) or 1 (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature) was required for inclusion in the trial.
Human Papillomavirus (HPV) Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 301 participants 281 participants 300 participants 882 participants
HPV Positive
63
  20.9%
60
  21.4%
67
  22.3%
190
  21.5%
HPV Negative
238
  79.1%
221
  78.6%
233
  77.7%
692
  78.5%
[1]
Measure Description: HPV status for oropharynx cancer as determined by p16 immunohistochemistry (IHC) (positive vs. negative); HPV status for participants without oropharynx cancer was considered HPV negative.
PD-L1 TPS Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 301 participants 281 participants 300 participants 882 participants
Strongly Positive
67
  22.3%
66
  23.5%
66
  22.0%
199
  22.6%
Not Strongly Positive
234
  77.7%
215
  76.5%
234
  78.0%
683
  77.4%
[1]
Measure Description: The Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) Status indicates the degree by which participants tumors stain positive for PD-L1 by IHC staining (i.e. strongly positive or not strongly positive). Participants with a TPS ≥50% were classified as PD-L1 "strongly positive" and participants with a TPS <50% were classified as "not strongly positive."
PD-L1 CPS ≥1 Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 301 participants 281 participants 300 participants 882 participants
CPS<1
44
  14.6%
39
  13.9%
45
  15.0%
128
  14.5%
CPS ≥1
257
  85.4%
242
  86.1%
255
  85.0%
754
  85.5%
[1]
Measure Description: The PD-L1 Combined Positive Score (CPS) Status indicates tumor PD-L1 positivity using both tumor cells and inflammatory cells that are positive for PD-L1 by IHC. The number of participants with CPS<1 and CPS≥1 at baseline is presented. Participants with a CPS<1 were classified as PD-L1 negative and participants with a CPS≥1 were classified as PD-L1 positive.
PD-L1 CPS ≥20 Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 301 participants 281 participants 300 participants 882 participants
CPS <20
167
  55.5%
154
  54.8%
175
  58.3%
496
  56.2%
CPS ≥20
133
  44.2%
126
  44.8%
122
  40.7%
381
  43.2%
Missing
1
   0.3%
1
   0.4%
3
   1.0%
5
   0.6%
[1]
Measure Description: The PD-L1 CPS Status indicates tumor PD-L1 positivity using both tumor cells and inflammatory cells that are positive for PD-L1 by IHC. The number of participants with CPS<20 and CPS ≥20 at baseline is presented.
1.Primary Outcome
Title Pembro Combo vs Control: Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in All Participants
Hide Description

PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro combo arm was compared to the control arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population. PFS is reported here for all participants in the pembro combo arm and control arm. Per protocol, PFS was compared separately between all participants of the pembro mono arm and control arm and is presented later in the record.

Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro combo arm or control arm during active enrollment were analyzed. 22 participants in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 281 278
Median (95% Confidence Interval)
Unit of Measure: Months
4.9
(4.7 to 6.1)
5.2
(4.9 to 6.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments PFS in all participants of the pembro combo arm was compared to PFS in all participants of the control arm to address the sixth primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.21211
Comments One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.78 to 1.11
Estimation Comments [Not Specified]
2.Primary Outcome
Title Pembro Combo vs Control: PFS Per RECIST 1.1 by BICR in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro combo arm was compared to the control arm as a pre-specified primary analysis of the ITT population. PFS is reported here for all participants in the pembro combo arm and control arm with PD-L1 biomarker positive expression defined by immunohistochemistry (IHC) as Combined Positive Score ≥1 (hereafter referred to as CPS ≥1). Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later in the record.

Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥1 were analyzed. 20 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 242 235
Median (95% Confidence Interval)
Unit of Measure: Months
5.1
(4.7 to 6.2)
5.0
(4.8 to 6.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments PFS in CPS ≥1 participants of the pembro combo arm was compared to PFS in CPS ≥1 participants of the control arm to address the fifth primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.03697
Comments One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.69 to 1.02
Estimation Comments [Not Specified]
3.Primary Outcome
Title Pembro Combo vs Control: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro combo arm was compared to the control arm as a pre-specified primary analysis of the ITT population. PFS is reported here for all participants in the pembro combo arm and control arm with PD-L1 biomarker positive expression defined by IHC as Combined Positive Score ≥20 (hereafter referred to as CPS ≥20). Per protocol, PFS was compared separately between CPS ≥20 participants of the pembro mono arm and control arm and is presented later in the record.

Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥20 were analyzed. 12 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 126 110
Median (95% Confidence Interval)
Unit of Measure: Months
5.8
(4.7 to 7.6)
5.3
(4.9 to 6.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments PFS in CPS ≥20 participants of the pembro combo arm was compared to PFS in CPS ≥20 participants of the control arm to address the fourth primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG and HPV status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02951
Comments One-sided p-value based on log-rank test stratified by ECOG and HPV status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.58 to 1.01
Estimation Comments [Not Specified]
4.Primary Outcome
Title Pembro Combo vs Control: Overall Survival (OS) in All Participants
Hide Description OS 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 in the pembro combo arm was compared to the control arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and control arm. Per protocol, OS was compared separately between all participants of the pembro mono arm and control arm and is presented later in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro combo arm or control arm during active enrollment were analyzed. 22 participants in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 281 278
Median (95% Confidence Interval)
Unit of Measure: Months
13.0
(10.9 to 14.7)
10.7
(9.3 to 11.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments OS in all participants of the pembro combo arm was compared to OS in all participants of the control arm to address the fourteenth primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00025
Comments One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
0.60 to 0.87
Estimation Comments [Not Specified]
5.Primary Outcome
Title Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥1
Hide Description OS 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 in the pembro combo arm was compared to the control arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and control arm with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. Per protocol, OS was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥1 were analyzed. 20 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 242 235
Median (95% Confidence Interval)
Unit of Measure: Months
13.6
(10.7 to 15.5)
10.4
(9.1 to 11.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments OS in CPS ≥1 participants of the pembro combo arm was compared to OS in CPS ≥1 participants of the control arm to address the twelfth primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00002
Comments One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.53 to 0.80
Estimation Comments [Not Specified]
6.Primary Outcome
Title Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥20
Hide Description OS 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 in the pembro combo arm was compared to the control arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and control arm with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. Per protocol, OS was compared separately between CPS ≥20 participants of the pembro mono arm and control arm and is presented later in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥20 were analyzed. 12 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 126 110
Median (95% Confidence Interval)
Unit of Measure: Months
14.7
(10.3 to 19.3)
11.0
(9.2 to 13.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments OS in CPS ≥20 participants of the pembro combo arm was compared to OS in CPS ≥20 participants of the control arm to address the eleventh primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG and HPV status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00044
Comments One-sided p-value based on log-rank test stratified by ECOG and HPV status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
0.45 to 0.82
Estimation Comments [Not Specified]
7.Primary Outcome
Title Pembro Mono vs Control: PFS Per RECIST 1.1 by BICR in All Participants
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro mono arm was compared to the control arm as a pre-specified primary analysis of the ITT population. PFS is reported here for all participants in the pembro mono arm and control arm. Per protocol, PFS was compared separately between all participants of the pembro combo arm and control arm and is presented earlier in the record.

Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 301 0 300
Median (95% Confidence Interval)
Unit of Measure: Months
2.3
(2.2 to 3.3)
5.2
(4.9 to 6.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments PFS in all participants of the pembro mono arm was compared to PFS in all participants of the control arm to address the third primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.99830
Comments One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.29
Confidence Interval (2-Sided) 95%
1.09 to 1.53
Estimation Comments [Not Specified]
8.Primary Outcome
Title Pembro Mono vs Control: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro mono arm was compared to the control arm as a pre-specified primary analysis of the ITT population. PFS is reported here for all participants in the pembro mono arm and control arm with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier in the record.

Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥1 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 257 0 255
Median (95% Confidence Interval)
Unit of Measure: Months
3.2
(2.2 to 3.4)
5.0
(4.8 to 6.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments PFS in CPS ≥1 participants of the pembro mono arm was compared to PFS in CPS ≥1 participants of the control arm to address the second primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.89580
Comments One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.13
Confidence Interval (2-Sided) 95%
0.94 to 1.36
Estimation Comments [Not Specified]
9.Primary Outcome
Title Pembro Mono vs Control: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro mono arm was compared to the control arm as a pre-specified primary analysis of the ITT population. PFS is reported here for all participants in the pembro mono arm and control arm with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. Per protocol, PFS was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier in the record.

Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥20 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 133 0 122
Median (95% Confidence Interval)
Unit of Measure: Months
3.4
(3.2 to 3.8)
5.3
(4.8 to 6.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments PFS in CPS ≥20 participants of the pembro mono arm was compared to PFS in CPS ≥20 participants of the control arm to address the first primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG and HPV status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.46791
Comments One-sided p-value based on log-rank test stratified by ECOG and HPV status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.76 to 1.29
Estimation Comments [Not Specified]
10.Primary Outcome
Title Pembro Mono vs Control: OS in All Participants
Hide Description OS 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 in the pembro mono arm was compared to the control arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and control arm. Per protocol, OS was compared separately between all participants of the pembro combo arm and control arm and is presented earlier in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 301 0 300
Median (95% Confidence Interval)
Unit of Measure: Months
11.5
(10.3 to 13.4)
10.7
(9.3 to 11.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments OS in all participants of the pembro mono arm was compared to OS in all participants of the control arm to address the tenth primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01985
Comments One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.70 to 0.99
Estimation Comments [Not Specified]
11.Primary Outcome
Title Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥1
Hide Description OS 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 in the pembro mono arm was compared to the control arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and control arm with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. Per protocol, OS was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥1 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 257 0 255
Median (95% Confidence Interval)
Unit of Measure: Months
12.3
(10.8 to 14.3)
10.3
(9.0 to 11.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments OS in CPS ≥1 participants of the pembro mono arm was compared to OS in CPS ≥1 participants of the control arm to address the eighth primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00133
Comments One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.61 to 0.90
Estimation Comments [Not Specified]
12.Primary Outcome
Title Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥20
Hide Description OS 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 in the pembro mono arm was compared to the control arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and control arm with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. Per protocol, OS was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥20 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 133 0 122
Median (95% Confidence Interval)
Unit of Measure: Months
14.8
(11.5 to 20.6)
10.7
(8.8 to 12.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments OS in CPS ≥20 participants of the pembro mono arm was compared to OS in CPS ≥20 participants of the control arm to address the seventh primary hypothesis. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG and HPV status.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00010
Comments One-sided p-value based on log-rank test stratified by ECOG and HPV status.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
0.44 to 0.78
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Pembro Combo vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among All Participants
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro combo arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 6 months is reported here out of all participants in the pembro combo arm and control arm. Per protocol, the percentage of participants with PFS at 6 months was compared separately between all participants of the pembro mono arm and control arm and is presented later in the record.

Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro combo arm or control arm during active enrollment were analyzed. 22 participants in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 281 278
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
44.7
(38.8 to 50.5)
44.9
(38.9 to 50.8)
14.Secondary Outcome
Title Pembro Combo vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro combo arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 6 months is reported here out of all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥1 in the pembro combo arm and control arm. Per protocol, the percentage of participants with PFS at 6 months was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later in the record.

Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥1 were analyzed. 20 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 242 235
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
44.9
(38.5 to 51.1)
43.3
(36.9 to 49.6)
15.Secondary Outcome
Title Pembro Combo vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro combo arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 6 months is reported here out of all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥20 in the pembro combo arm and control arm. Per protocol, the percentage of participants with PFS at 6 months was compared separately between CPS ≥20 participants of the pembro mono arm and control arm and is presented later in the record.

Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥20 were analyzed. 12 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 126 110
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
49.4
(40.3 to 57.9)
47.2
(37.5 to 56.2)
16.Secondary Outcome
Title Pembro Combo vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among All Participants
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro combo arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 12 months is reported here out of all participants in the pembro combo arm and control arm. Per protocol, the percentage of participants with PFS at 12 months was compared separately between all participants of the pembro mono arm and control arm and is presented later in the record.

Time Frame Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro combo arm or control arm during active enrollment were analyzed. 22 participants in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 281 278
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
17.2
(13.0 to 21.9)
13.6
(9.8 to 18.1)
17.Secondary Outcome
Title Pembro Combo vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro combo arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 12 months is reported here out of all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥1 in the pembro combo arm and control arm. Per protocol, the percentage of participants with PFS at 12 months was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later in the record.

Time Frame Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥1 were analyzed. 20 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 242 235
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
19.7
(14.8 to 25.0)
12.5
(8.6 to 17.3)
18.Secondary Outcome
Title Pembro Combo vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro combo arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 12 months is reported here out of all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥20 in the pembro combo arm and control arm. Per protocol, the percentage of participants with PFS at 12 months was compared separately between CPS ≥20 participants of the pembro mono arm and control arm and is presented later in the record.

Time Frame Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥20 were analyzed. 12 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 126 110
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
23.9
(16.7 to 31.7)
14.0
(8.2 to 21.3)
19.Secondary Outcome
Title Pembro Combo vs Control: Objective Response Rate (ORR) Per RECIST 1.1 by BICR in All Participants
Hide Description ORR was defined as the percentage of participants in the analysis population who have 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. based upon BICR. Per protocol, ORR in the pembro combo arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro combo arm and control arm. Per protocol, ORR was compared separately between all participants of the pembro mono arm and control arm and is presented later in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro combo arm or control arm during active enrollment were analyzed. 22 participants in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 281 278
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
35.6
(30.0 to 41.5)
36.3
(30.7 to 42.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments ORR in all participants of the pembro combo arm was compared to ORR in all participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5740
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in ORR Percentage
Estimated Value -0.8
Confidence Interval (2-Sided) 95%
-8.7 to 7.2
Estimation Comments [Not Specified]
20.Secondary Outcome
Title Pembro Combo vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1
Hide Description ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro combo arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥1 in the pembro combo arm and control arm. Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥1 were analyzed. 20 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 242 235
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
36.4
(30.3 to 42.8)
35.7
(29.6 to 42.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments ORR in CPS ≥1 participants of the pembro combo arm was compared to ORR in CPS ≥1 participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4586
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in ORR Percentage
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
-8.2 to 9.1
Estimation Comments [Not Specified]
21.Secondary Outcome
Title Pembro Combo vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20
Hide Description ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro combo arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥20 in the pembro combo arm and control arm. Per protocol, ORR was compared separately between CPS ≥20 participants of the pembro mono arm and control arm and is presented later in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population randomized to either pembro combo arm or control arm during active enrollment with CPS ≥20 were analyzed. 12 participants in control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 126 110
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
42.9
(34.1 to 52.0)
38.2
(29.1 to 47.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments ORR in CPS ≥20 participants of the pembro combo arm was compared to ORR in CPS ≥20 participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1) and HPV status (Positive vs. Negative).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2161
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in ORR Percentage
Estimated Value 5.0
Confidence Interval (2-Sided) 95%
-7.5 to 17.4
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Pembro Combo vs Control: Change From Baseline to Week 15 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score
Hide 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 15 in the GHS/QoL combined score was compared between all participants of the pembro combo arm and the control arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 15 in the GHS/QoL combined score was compared separately between all participants of the pembro mono arm and control arm and is presented later in the record.
Time Frame Baseline, Week 15
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in pembro combo arm and control arm who received ≥1 dose of study drug and with EORTC-QLQ-C30 assessments available at baseline or post-baseline up to Week 15. 20 in control arm enrolled during enrollment pause of the pembro combo arm were excluded. Per protocol, pembro mono arm compared to control arm separately and not included here.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 268 259
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Score on a Scale
1.17
(-1.79 to 4.12)
0.77
(-2.22 to 3.76)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments Change from baseline to Week 15 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro combo arm and the control arm. Comparison based on constrained longitudinal data analysis (cLDA) model with GHS/QoL score as response variable and treatment by visit interaction, stratification factors (ECOG [0 vs. 1], HPV status [Positive vs. Negative] and PD-L1 TPS status [Strongly Positive, Not Strongly Positive]) as covariates.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.839
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method constrained Longitudinal Data Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in LS Means
Estimated Value 0.40
Confidence Interval (2-Sided) 95%
-3.46 to 4.26
Estimation Comments [Not Specified]
23.Secondary Outcome
Title Pembro Combo vs Control: Time to Deterioration (TTD) in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score (Kaplan-Meier Method)
Hide Description EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the GHS question "How would you rate your overall health during the past week?" (Item 29) and the 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). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL defined as the time from baseline to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score, with confirmation. Per protocol, TTD in GHS/QoL combined score was compared between all participants of pembro combo arm and control arm as a pre-specified secondary analysis. Also per protocol, TTD in GHS/QoL combined score was compared separately between all participants of pembro mono arm and control arm and is presented later in the record.
Time Frame Baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the pembro combo arm and the control arm who completed the EORTC QLQ-C30 and had received ≥1 dose of study drug. 20 in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, the pembro mono arm was compared to the control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 270 260
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA=Median and 95% confidence interval limits not reached due to an insufficient number of participants with the event.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments TTD in GHS/QoL combined score was compared between all participants of the pembro combo arm and the control arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9497
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.37
Confidence Interval (2-Sided) 95%
0.94 to 2.00
Estimation Comments [Not Specified]
24.Secondary Outcome
Title Pembro Combo vs Control: TTD in the EORTC QLQ- Head and Neck Module 35 (H&N35) Pain Score (Kaplan-Meier Method)
Hide Description EORTC QLQ-H&N35 is a 35-item questionnaire developed to assess QoL of head and neck cancer participants and consists of 7 multi-item scales that assess pain, swallowing, senses, speech, social eating, social contact and sexuality. Participant responses to the Pain scale (Items 31-34) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. TTD in EORTC QLQ-H&N35 Pain Score defined as the time from baseline to the first onset of a ≥10 point decrease from baseline, with confirmation. Per protocol, TTD in EORTC QLQ-H&N35 Pain Score was compared between all participants of pembro combo arm and control arm as a pre-specified secondary analysis. Also per protocol, TTD in EORTC QLQ-H&N35 Pain Score was compared separately between all participants of pembro mono arm and control arm and is presented later in the record.
Time Frame Baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the pembro combo arm and control arm who completed the EORTC QLQ-H&N35 and had received ≥1 dose of study drug. 20 in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, the pembro mono arm was compared to the control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 268 260
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA=Median and 95% confidence interval limits not reached due to an insufficient number of participants with the event.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments TTD in EORTC QLQ-H&N35 Pain Score was compared between all participants of the pembro combo arm and the control arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9476
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.37
Confidence Interval (2-Sided) 95%
0.93 to 2.02
Estimation Comments [Not Specified]
25.Secondary Outcome
Title Pembro Combo vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score (Kaplan-Meier Method)
Hide Description EORTC QLQ-H&N35 is a 35-item questionnaire developed to assess QoL of head and neck cancer participants and consists of 7 multi-item scales that assess pain, swallowing, senses, speech, social eating, social contact and sexuality. Participant responses to the Swallowing scale (Items 35-38) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. TTD in EORTC QLQ-H&N35 Swallowing Score defined as the time from baseline to the first onset of a ≥10 point decrease from baseline, with confirmation. Per protocol, TTD in EORTC QLQ-H&N35 Swallowing Score was compared between all participants of pembro combo arm and control arm as a pre-specified secondary analysis. Also per protocol, TTD in EORTC QLQ-H&N35 Swallowing Score was compared separately between all participants of pembro mono arm and control arm and is presented later in the record.
Time Frame Baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the pembro combo arm and control arm who completed the EORTC QLQ-H&N35 and had received ≥1 dose of study drug. 20 in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. Per protocol, the pembro mono arm was compared to the control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 0 268 260
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA=Median and 95% confidence interval limits not reached due to an insufficient number of participants with the event.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Chemotherapy (Pembro Combo), Cetuximab + Chemotherapy (Control)
Comments TTD in EORTC QLQ-H&N35 Swallowing Score was compared between all participants of the pembro combo arm and the control arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5836
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
0.69 to 1.59
Estimation Comments [Not Specified]
26.Secondary Outcome
Title Pembro Mono vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among All Participants
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro mono arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 6 months is reported here out of all participants in the pembro mono arm and control arm. Per protocol, the percentage of participants with PFS at 6 months was compared separately between all participants of the pembro combo arm and control arm and is presented earlier in the record.

Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 301 0 300
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
26.2
(21.4 to 31.3)
45.7
(39.9 to 51.3)
27.Secondary Outcome
Title Pembro Mono vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro mono arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 6 months is reported here out of all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥1 in the pembro mono arm and control arm. Per protocol, the percentage of participants with PFS at 6 months was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier in the record.

Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥1 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 257 0 255
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
28.7
(23.3 to 34.4)
43.9
(37.6 to 49.9)
28.Secondary Outcome
Title Pembro Mono vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro mono arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 6 months is reported here out of all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥20 in the pembro mono arm and control arm. Per protocol, the percentage of participants with PFS at 6 months was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier in the record.

Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥20 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 133 0 122
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
33.0
(25.2 to 41.0)
46.6
(37.5 to 55.2)
29.Secondary Outcome
Title Pembro Mono vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among All Participants
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro mono arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 12 months is reported here out of all participants in the pembro mono arm and control arm. Per protocol, the percentage of participants with PFS at 12 months was compared separately between all participants of the pembro combo arm and control arm and is presented earlier in the record.

Time Frame Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 301 0 300
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
17.6
(13.5 to 22.1)
15.0
(11.2 to 19.4)
30.Secondary Outcome
Title Pembro Mono vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro mono arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 12 months is reported here out of all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥1 in the pembro mono arm and control arm. Per protocol, the percentage of participants with PFS at 12 months was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier in the record.

Time Frame Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥1 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 257 0 255
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
20.6
(15.9 to 25.8)
13.6
(9.6 to 18.2)
31.Secondary Outcome
Title Pembro Mono vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20
Hide Description

PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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.

Per protocol, PFS in the pembro mono arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants with PFS (PFS rate) at 12 months is reported here out of all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥20 in the pembro mono arm and control arm. Per protocol, the percentage of participants with PFS at 12 months was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier in the record.

Time Frame Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥20 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 133 0 122
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
23.5
(16.6 to 31.1)
15.1
(9.3 to 22.2)
32.Secondary Outcome
Title Pembro Mono vs Control: ORR Per RECIST 1.1 by BICR in All Participants
Hide Description ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro mono arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro mono arm and control arm. Per protocol, ORR was compared separately between all participants of the pembro combo arm and control arm and is presented earlier in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 301 0 300
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
16.9
(12.9 to 21.7)
36.0
(30.6 to 41.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments ORR in all participants of the pembro mono arm was compared to ORR in all participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive , Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0000
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in ORR Percentage
Estimated Value -19.0
Confidence Interval (2-Sided) 95%
-25.8 to -12.1
Estimation Comments [Not Specified]
33.Secondary Outcome
Title Pembro Mono vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1
Hide Description ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro mono arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥1 in the pembro mono arm and control arm. Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥1 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 257 0 255
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
19.1
(14.5 to 24.4)
34.9
(29.1 to 41.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments ORR in CPS ≥1 participants of the pembro mono arm was compared to ORR in CPS ≥1 participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0000
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in ORR Percentage
Estimated Value -15.9
Confidence Interval (2-Sided) 95%
-23.4 to -8.3
Estimation Comments [Not Specified]
34.Secondary Outcome
Title Pembro Mono vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20
Hide Description ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro mono arm was compared to the control arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants with PD-L1 biomarker positive expression defined by IHC as CPS ≥20 in the pembro mono arm and control arm. Per protocol, ORR was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier in the record.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the ITT population randomized to either the pembro mono arm or control arm during active enrollment with CPS ≥20 were analyzed. Per protocol, pembro combo arm was compared to control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 133 0 122
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
23.3
(16.4 to 31.4)
36.1
(27.6 to 45.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments ORR in CPS ≥20 participants of the pembro mono arm was compared to ORR in CPS ≥20 participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1) and HPV status (Positive vs. Negative).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9869
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Miettinen & Nurminen method
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in ORR Percentage
Estimated Value -12.8
Confidence Interval (2-Sided) 95%
-23.8 to -1.5
Estimation Comments [Not Specified]
35.Secondary Outcome
Title Pembro Mono vs Control: Change From Baseline to Week 15 in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score
Hide Description The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the GHS question "How would you rate your overall health during the past week?" (Item 29) and the 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 15 in the GHS/QoL combined score was compared between all participants of the pembro mono arm and the control arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 15 in the GHS/QoL combined score was compared separately between all participants of the pembro combo arm and control arm and is presented earlier in the record.
Time Frame Baseline, Week 15
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the pembro mono arm and the control arm who received ≥1 dose of study drug and had EORTC-QLQ-C30 assessments available at baseline or post-baseline up to Week 15. Per protocol, the pembro combo arm was compared to the control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 294 0 279
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Score on a Scale
0.85
(-1.90 to 3.59)
0.60
(-2.19 to 3.40)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments Change from baseline to Week 15 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro mono arm and the control arm. Comparison based on cLDA model with GHS/QoL score as response variable and treatment by visit interaction, stratification factors (ECOG [0 vs. 1], HPV status [Positive vs. Negative] and PD-L1 TPS status [Strongly Positive, Not Strongly Positive]) as covariates.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.893
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method constrained Longitudinal Data Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in LS Means
Estimated Value 0.24
Confidence Interval (2-Sided) 95%
-3.34 to 3.82
Estimation Comments [Not Specified]
36.Secondary Outcome
Title Pembro Mono vs Control: TTD in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score
Hide Description EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the GHS question "How would you rate your overall health during the past week?" (Item 29) and the 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). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL defined as the time from baseline to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score, with confirmation. Per protocol, TTD in GHS/QoL combined score was compared between all participants of pembro mono arm and control arm as a pre-specified secondary analysis. Also per protocol, TTD in GHS/QoL combined score was compared separately between all participants of pembro combo arm and control arm and is presented earlier in the record.
Time Frame Baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the pembro mono arm and the control arm who completed the EORTC QLQ-C30 and had received ≥1 dose of study drug. Per protocol, the pembro combo arm was compared to the control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 294 0 280
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA=Median and 95% confidence interval limits not reached due to an insufficient number of participants with the event.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments TTD in GHS/QoL combined score was compared between all participants of the pembro mono arm and the control arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9530
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.38
Confidence Interval (2-Sided) 95%
0.95 to 2.00
Estimation Comments [Not Specified]
37.Secondary Outcome
Title Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Pain Score
Hide Description EORTC QLQ-H&N35 is a 35-item questionnaire developed to assess QoL of head and neck cancer participants and consists of 7 multi-item scales that assess pain, swallowing, senses, speech, social eating, social contact and sexuality. Participant responses to the Pain scale (Items 31-34) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. TTD in EORTC QLQ-H&N35 Pain Score defined as the time from baseline to the first onset of a ≥10 point decrease from baseline, with confirmation. Per protocol, TTD in EORTC QLQ-H&N35 Pain Score was compared between all participants of pembro mono arm and control arm as a pre-specified secondary analysis. Also per protocol, TTD in EORTC QLQ-H&N35 Pain Score was compared separately between all participants of pembro combo arm and control arm and is presented earlier in the record.
Time Frame Baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the pembro mono arm and control arm who completed the EORTC QLQ-H&N35 and had received ≥1 dose of study drug. Per protocol, the pembro combo arm was compared to the control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 295 0 280
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA=Median and 95% confidence interval limits not reached due to an insufficient number of participants with the event.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments TTD in EORTC QLQ-H&N35 Pain Score was compared between all participants of the pembro mono arm and the control arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1501
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.53 to 1.21
Estimation Comments [Not Specified]
38.Secondary Outcome
Title Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score
Hide Description EORTC QLQ-H&N35 is a 35-item questionnaire developed to assess QoL of head and neck cancer participants and consists of 7 multi-item scales that assess pain, swallowing, senses, speech, social eating, social contact and sexuality. Participant responses to the Swallowing scale (Items 35-38) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. TTD in EORTC QLQ-H&N35 Swallowing Score defined as the time from baseline to the first onset of a ≥10 point decrease from baseline, with confirmation. Per protocol, TTD in EORTC QLQ-H&N35 Swallowing Score was compared between all participants of pembro mono arm and control arm as a pre-specified secondary analysis. Also per protocol, TTD in EORTC QLQ-H&N35 Swallowing Score was compared separately between all participants of pembro combo arm and control arm and is presented earlier in the record.
Time Frame Baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in the pembro mono arm and control arm who completed the EORTC QLQ-H&N35 and had received ≥1 dose of study drug. Per protocol, the pembro combo arm was compared to the control arm separately and not included in this analysis.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 295 0 280
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
NA=Median and 95% confidence interval limits not reached due to an insufficient number of participants with the event.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pembrolizumab Monotherapy (Pembro Mono), Cetuximab + Chemotherapy (Control)
Comments TTD in EORTC QLQ-H&N35 Swallowing Score was compared between all participants of the pembro mono arm and the control arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8751
Comments No formal hypothesis testing performed; nominal p-value provided for treatment comparison.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.26
Confidence Interval (2-Sided) 95%
0.85 to 1.88
Estimation Comments [Not Specified]
39.Secondary Outcome
Title Number of Participants Experiencing an Adverse Event (AE)
Hide 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.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received ≥1 dose of study drug.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 300 276 287
Measure Type: Count of Participants
Unit of Measure: Participants
290
  96.7%
271
  98.2%
286
  99.7%
40.Secondary Outcome
Title Number of Participants Who Discontinued Study Drug Due to an AE
Hide 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 study drug due to an AE was reported for each treatment arm.
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received ≥1 dose of study drug.
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description:
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.
Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Overall Number of Participants Analyzed 300 276 287
Measure Type: Count of Participants
Unit of Measure: Participants
36
  12.0%
90
  32.6%
79
  27.5%
Time Frame Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)
Adverse Event Reporting Description

All-Cause Mortality table reported for all randomized participants.

Serious AEs table and Other AEs table were reported for all randomized participants who received at least 1 dose of study treatment. Per protocol, disease progression of cancer on study was not considered an AE unless considered related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.

 
Arm/Group Title Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Hide Arm/Group Description Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months. Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum). Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
All-Cause Mortality
Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   237/301 (78.74%)      214/281 (76.16%)      265/300 (88.33%)    
Hide Serious Adverse Events
Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   123/300 (41.00%)      165/276 (59.78%)      141/287 (49.13%)    
Blood and lymphatic system disorders       
Anaemia  1  1/300 (0.33%)  1 14/276 (5.07%)  17 9/287 (3.14%)  11
Anaemia of chronic disease  1  0/300 (0.00%)  0 1/276 (0.36%)  2 0/287 (0.00%)  0
Disseminated intravascular coagulation  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Febrile neutropenia  1  0/300 (0.00%)  0 17/276 (6.16%)  17 15/287 (5.23%)  16
Haematotoxicity  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Leukopenia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 1/287 (0.35%)  1
Lymphadenitis  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Neutropenia  1  0/300 (0.00%)  0 6/276 (2.17%)  6 4/287 (1.39%)  6
Pancytopenia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 1/287 (0.35%)  1
Thrombocytopenia  1  0/300 (0.00%)  0 6/276 (2.17%)  6 0/287 (0.00%)  0
Cardiac disorders       
Acute myocardial infarction  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Angina pectoris  1  1/300 (0.33%)  1 1/276 (0.36%)  1 0/287 (0.00%)  0
Atrial fibrillation  1  1/300 (0.33%)  1 1/276 (0.36%)  1 3/287 (1.05%)  3
Autoimmune myocarditis  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Cardiac arrest  1  0/300 (0.00%)  0 2/276 (0.72%)  2 0/287 (0.00%)  0
Cardiac failure  1  0/300 (0.00%)  0 2/276 (0.72%)  2 0/287 (0.00%)  0
Cardiac failure acute  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Cardiopulmonary failure  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Myocardial infarction  1  3/300 (1.00%)  3 3/276 (1.09%)  3 3/287 (1.05%)  3
Myocardial ischaemia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Palpitations  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Supraventricular extrasystoles  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Supraventricular tachycardia  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Tachycardia  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Endocrine disorders       
Adrenal insufficiency  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Hypercalcaemia of malignancy  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Hyperthyroidism  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Hypophysitis  1  0/300 (0.00%)  0 1/276 (0.36%)  2 0/287 (0.00%)  0
Hypopituitarism  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain  1  1/300 (0.33%)  1 2/276 (0.72%)  2 1/287 (0.35%)  1
Abdominal pain upper  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Colitis  1  0/300 (0.00%)  0 1/276 (0.36%)  1 2/287 (0.70%)  2
Colitis microscopic  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Constipation  1  2/300 (0.67%)  2 1/276 (0.36%)  1 0/287 (0.00%)  0
Diarrhoea  1  2/300 (0.67%)  2 1/276 (0.36%)  1 4/287 (1.39%)  4
Duodenal ulcer  1  1/300 (0.33%)  1 0/276 (0.00%)  0 1/287 (0.35%)  1
Dysphagia  1  4/300 (1.33%)  4 2/276 (0.72%)  2 1/287 (0.35%)  1
Enteritis  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Enterocolitis  1  2/300 (0.67%)  2 0/276 (0.00%)  0 0/287 (0.00%)  0
Gastric haemorrhage  1  1/300 (0.33%)  1 1/276 (0.36%)  1 1/287 (0.35%)  1
Gastric perforation  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Gastric ulcer  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Gastritis  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Gastrointestinal toxicity  1  1/300 (0.33%)  1 0/276 (0.00%)  0 1/287 (0.35%)  1
Haematemesis  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Haematochezia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Haemorrhoids  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Intestinal obstruction  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Intestinal perforation  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Lower gastrointestinal haemorrhage  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Mouth haemorrhage  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Nausea  1  0/300 (0.00%)  0 6/276 (2.17%)  6 8/287 (2.79%)  9
Oesophageal fistula  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Oral cavity fistula  1  1/300 (0.33%)  1 0/276 (0.00%)  0 1/287 (0.35%)  1
Pancreatitis acute  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Peptic ulcer haemorrhage  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Pneumatosis intestinalis  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Pneumoperitoneum  1  1/300 (0.33%)  1 0/276 (0.00%)  0 1/287 (0.35%)  1
Stomatitis  1  0/300 (0.00%)  0 8/276 (2.90%)  8 4/287 (1.39%)  4
Tongue oedema  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Umbilical hernia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Upper gastrointestinal haemorrhage  1  1/300 (0.33%)  1 0/276 (0.00%)  0 3/287 (1.05%)  3
Vomiting  1  0/300 (0.00%)  0 5/276 (1.81%)  5 5/287 (1.74%)  5
General disorders       
Asthenia  1  1/300 (0.33%)  1 0/276 (0.00%)  0 2/287 (0.70%)  2
Catheter site inflammation  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Chest pain  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Complication associated with device  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Death  1  2/300 (0.67%)  2 2/276 (0.72%)  2 2/287 (0.70%)  2
Fatigue  1  3/300 (1.00%)  3 1/276 (0.36%)  1 3/287 (1.05%)  3
General physical health deterioration  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Hyperthermia  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Localised oedema  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Mucosal inflammation  1  1/300 (0.33%)  1 6/276 (2.17%)  6 1/287 (0.35%)  1
Multiple organ dysfunction syndrome  1  2/300 (0.67%)  2 2/276 (0.72%)  2 0/287 (0.00%)  0
Peripheral swelling  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Pneumatosis  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Pyrexia  1  2/300 (0.67%)  2 7/276 (2.54%)  7 1/287 (0.35%)  1
Sudden death  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Swelling  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Hepatobiliary disorders       
Autoimmune hepatitis  1  2/300 (0.67%)  2 1/276 (0.36%)  1 0/287 (0.00%)  0
Cholecystitis acute  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Immune system disorders       
Anaphylactic reaction  1  1/300 (0.33%)  1 0/276 (0.00%)  0 2/287 (0.70%)  2
Autoinflammatory disease  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Hypersensitivity  1  1/300 (0.33%)  1 1/276 (0.36%)  1 1/287 (0.35%)  1
Type III immune complex mediated reaction  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Infections and infestations       
Abdominal infection  1  0/300 (0.00%)  0 0/276 (0.00%)  0 2/287 (0.70%)  2
Abscess limb  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Abscess neck  1  1/300 (0.33%)  1 0/276 (0.00%)  0 1/287 (0.35%)  1
Arthritis bacterial  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Atypical pneumonia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Bacteraemia  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Bronchitis  1  2/300 (0.67%)  2 3/276 (1.09%)  4 2/287 (0.70%)  2
Cellulitis  1  2/300 (0.67%)  2 2/276 (0.72%)  2 1/287 (0.35%)  2
Cytomegalovirus gastrointestinal infection  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Device related infection  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Device related sepsis  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Encephalitis  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Epidural empyema  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Escherichia bacteraemia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Escherichia infection  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Gastroenteritis  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Gastroenteritis norovirus  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Gastrointestinal viral infection  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Herpes zoster  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Infection  1  1/300 (0.33%)  1 1/276 (0.36%)  1 1/287 (0.35%)  1
Infective exacerbation of chronic obstructive airways disease  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Influenza  1  0/300 (0.00%)  0 1/276 (0.36%)  1 1/287 (0.35%)  1
Klebsiella sepsis  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Laryngitis  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Lower respiratory tract infection  1  0/300 (0.00%)  0 1/276 (0.36%)  1 1/287 (0.35%)  1
Lung infection  1  3/300 (1.00%)  5 7/276 (2.54%)  7 2/287 (0.70%)  2
Lung infection pseudomonal  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Medical device site abscess  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Medical device site infection  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Neutropenic sepsis  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Oral candidiasis  1  2/300 (0.67%)  2 0/276 (0.00%)  0 0/287 (0.00%)  0
Osteomyelitis  1  0/300 (0.00%)  0 0/276 (0.00%)  0 2/287 (0.70%)  2
Otitis media  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Penile infection  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Peritonitis  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Pneumonia  1  18/300 (6.00%)  20 16/276 (5.80%)  18 18/287 (6.27%)  22
Pneumonia bacterial  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Pneumonia staphylococcal  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Pseudomonal sepsis  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Pulmonary sepsis  1  1/300 (0.33%)  1 1/276 (0.36%)  1 0/287 (0.00%)  0
Respiratory tract infection  1  1/300 (0.33%)  1 4/276 (1.45%)  5 1/287 (0.35%)  1
Sepsis  1  6/300 (2.00%)  6 4/276 (1.45%)  4 2/287 (0.70%)  2
Septic shock  1  1/300 (0.33%)  1 6/276 (2.17%)  6 2/287 (0.70%)  2
Skin infection  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Soft tissue infection  1  3/300 (1.00%)  4 0/276 (0.00%)  0 1/287 (0.35%)  1
Staphylococcal infection  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Staphylococcal sepsis  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Stoma site infection  1  1/300 (0.33%)  1 1/276 (0.36%)  1 2/287 (0.70%)  2
Tracheitis  1  1/300 (0.33%)  2 2/276 (0.72%)  2 0/287 (0.00%)  0
Tracheobronchitis  1  1/300 (0.33%)  1 1/276 (0.36%)  1 0/287 (0.00%)  0
Tracheostomy infection  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Upper respiratory tract infection  1  0/300 (0.00%)  0 1/276 (0.36%)  1 1/287 (0.35%)  1
Urinary tract infection  1  0/300 (0.00%)  0 1/276 (0.36%)  1 3/287 (1.05%)  3
Vascular device infection  1  2/300 (0.67%)  2 1/276 (0.36%)  1 3/287 (1.05%)  3
Viral infection  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Wound infection  1  1/300 (0.33%)  1 0/276 (0.00%)  0 1/287 (0.35%)  1
Wound sepsis  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Injury, poisoning and procedural complications       
Alcohol poisoning  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Ankle fracture  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Arterial injury  1  1/300 (0.33%)  1 1/276 (0.36%)  1 0/287 (0.00%)  0
Contusion  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Fall  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Femur fracture  1  0/300 (0.00%)  0 0/276 (0.00%)  0 2/287 (0.70%)  2
Gastrointestinal stoma complication  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Gastrostomy failure  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Head injury  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Heat stroke  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Hip fracture  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Infusion related reaction  1  0/300 (0.00%)  0 1/276 (0.36%)  1 3/287 (1.05%)  3
Osteoradionecrosis  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Post procedural haemorrhage  1  1/300 (0.33%)  1 1/276 (0.36%)  1 0/287 (0.00%)  0
Spinal compression fracture  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Stoma site extravasation  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Stoma site pain  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Synovial rupture  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Tibia fracture  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Tracheal obstruction  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Tracheostomy malfunction  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Traumatic fracture  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  2
Investigations       
Alanine aminotransferase increased  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Aspartate aminotransferase increased  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Blood calcium increased  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Blood creatinine increased  1  0/300 (0.00%)  0 3/276 (1.09%)  3 0/287 (0.00%)  0
Blood potassium decreased  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
C-reactive protein increased  1  1/300 (0.33%)  2 0/276 (0.00%)  0 0/287 (0.00%)  0
Glomerular filtration rate decreased  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Neutrophil count decreased  1  0/300 (0.00%)  0 0/276 (0.00%)  0 3/287 (1.05%)  3
Platelet count decreased  1  0/300 (0.00%)  0 3/276 (1.09%)  3 1/287 (0.35%)  1
Transaminases increased  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Weight decreased  1  2/300 (0.67%)  2 1/276 (0.36%)  1 1/287 (0.35%)  1
White blood cell count decreased  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  1
Metabolism and nutrition disorders       
Decreased appetite  1  1/300 (0.33%)  1 5/276 (1.81%)  7 4/287 (1.39%)  4
Dehydration  1  1/300 (0.33%)  1 6/276 (2.17%)  6 4/287 (1.39%)  4
Electrolyte imbalance  1  1/300 (0.33%)  1 1/276 (0.36%)  1 0/287 (0.00%)  0
Hypercalcaemia  1  4/300 (1.33%)  4 3/276 (1.09%)  3 2/287 (0.70%)  2
Hyperglycaemia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Hyperglycaemic hyperosmolar nonketotic syndrome  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Hyperkalaemia  1  0/300 (0.00%)  0 0/276 (0.00%)  0 1/287 (0.35%)  2
Hyperuricaemia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 0/287 (0.00%)  0
Hypocalcaemia  1  0/300 (0.00%)  0 1/276 (0.36%)  1 1/287 (0.35%)  1
Hypokalaemia  1  1/300 (0.33%)  1 4/276 (1.45%)  4 1/287 (0.35%)  1
Hypomagnesaemia  1  0/300 (0.00%)  0 2/276 (0.72%)  2 1/287 (0.35%)  1
Hyponatraemia  1  1/300 (0.33%)  1 7/276 (2.54%)  7 2/287 (0.70%)  2
Malnutrition  1  2/300 (0.67%)  2 0/276 (0.00%)  0 1/287 (0.35%)  1
Musculoskeletal and connective tissue disorders       
Arthralgia  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Arthritis  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Arthropathy  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Fistula  1  1/300 (0.33%)  1 0/276 (0.00%)  0 1/287 (0.35%)  1
Joint swelling  1  1/300 (0.33%)  1 0/276 (0.00%)  0 0/287 (0.00%)  0
Neck pain  1  1/300 (0.33%)  2 0/276 (0.00%)  0 1/287 (0.35%)  1
Polyarthritis  1