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)

• ClinicalTrials.gov Identifier: NCT02358031
• Recruitment Status: Completed
• First Posted: February 6, 2015
• Results First Posted: February 17, 2020
• Last Update Posted: February 12, 2024
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

• 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

Participant Flow

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)
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

Baseline Characteristics

Arm/Group Title		Pembrolizumab Monotherapy (Pembro Mono)	Pembrolizumab + Chemotherapy (Pembro Combo)	Cetuximab + Chemotherapy (Control)	Total
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
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.

Outcome Measures

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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

Outcome Measure Data

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)
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)

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)
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

Outcome Measure Data

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)
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.

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)
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

Outcome Measure Data

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)
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.

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)
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

Outcome Measure Data

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)
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.

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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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

Outcome Measure Data

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)
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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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)

Outcome Measure Data

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)
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)

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
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

Outcome Measure Data

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)
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)

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
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

Outcome Measure Data

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)
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.

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
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

Outcome Measure Data

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)
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.

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
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

Outcome Measure Data

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)
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.

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)
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)

Outcome Measure Data

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)
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
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)

Outcome Measure Data

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)
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%

Adverse Events

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)
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%)
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	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Rhabdomyolysis † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Synovial cyst † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Cancer pain † 1	2/300 (0.67%)	2	1/276 (0.36%)	1	1/287 (0.35%)	1
Haemorrhagic tumour necrosis † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Infected neoplasm † 1	3/300 (1.00%)	3	1/276 (0.36%)	1	2/287 (0.70%)	2
Metastases to bone † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Prostate cancer † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Squamous cell carcinoma of the oral cavity † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Tumour flare † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Tumour haemorrhage † 1	11/300 (3.67%)	13	6/276 (2.17%)	7	5/287 (1.74%)	5
Tumour pain † 1	1/300 (0.33%)	1	1/276 (0.36%)	1	0/287 (0.00%)	0
Nervous system disorders
Carotid artery perforation † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Carotid sinus syndrome † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Cauda equina syndrome † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Cerebral infarction † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Cerebral ischaemia † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Cerebrovascular accident † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	2/287 (0.70%)	2
Embolic stroke † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Hemiparesis † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Ischaemic stroke † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Presyncope † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Restless legs syndrome † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Seizure † 1	1/300 (0.33%)	1	1/276 (0.36%)	1	1/287 (0.35%)	1
Spinal cord compression † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Syncope † 1	0/300 (0.00%)	0	2/276 (0.72%)	2	5/287 (1.74%)	5
Toxic encephalopathy † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Vocal cord paralysis † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Product Issues
Device dislocation † 1	0/300 (0.00%)	0	2/276 (0.72%)	2	1/287 (0.35%)	1
Device leakage † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Device occlusion † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Stent malfunction † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Psychiatric disorders
Anxiety † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Completed suicide † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Delirium † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Stress † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Suicide attempt † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	4/300 (1.33%)	4	5/276 (1.81%)	5	1/287 (0.35%)	1
Renal failure † 1	0/300 (0.00%)	0	3/276 (1.09%)	3	2/287 (0.70%)	2
Renal impairment † 1	0/300 (0.00%)	0	1/276 (0.36%)	2	0/287 (0.00%)	0
Renal tubular necrosis † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Tubulointerstitial nephritis † 1	2/300 (0.67%)	2	0/276 (0.00%)	0	0/287 (0.00%)	0
Urinary retention † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Aspiration † 1	2/300 (0.67%)	2	0/276 (0.00%)	0	0/287 (0.00%)	0
Bronchial obstruction † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Chronic obstructive pulmonary disease † 1	1/300 (0.33%)	1	1/276 (0.36%)	1	0/287 (0.00%)	0
Dyspnoea † 1	7/300 (2.33%)	9	2/276 (0.72%)	2	2/287 (0.70%)	2
Epistaxis † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Haemoptysis † 1	1/300 (0.33%)	1	1/276 (0.36%)	1	0/287 (0.00%)	0
Hydrothorax † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Hypoxia † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	1/287 (0.35%)	1
Interstitial lung disease † 1	1/300 (0.33%)	1	3/276 (1.09%)	3	1/287 (0.35%)	1
Laryngeal fistula † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Laryngeal obstruction † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Laryngeal oedema † 1	1/300 (0.33%)	1	4/276 (1.45%)	5	1/287 (0.35%)	2
Lung infiltration † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Pharyngeal haemorrhage † 1	1/300 (0.33%)	1	2/276 (0.72%)	2	0/287 (0.00%)	0
Pleural effusion † 1	2/300 (0.67%)	2	3/276 (1.09%)	3	0/287 (0.00%)	0
Pneumonia aspiration † 1	5/300 (1.67%)	5	8/276 (2.90%)	10	3/287 (1.05%)	3
Pneumonitis † 1	3/300 (1.00%)	3	2/276 (0.72%)	2	1/287 (0.35%)	1
Pneumothorax † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	1/287 (0.35%)	1
Pulmonary artery thrombosis † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Pulmonary embolism † 1	2/300 (0.67%)	2	4/276 (1.45%)	4	6/287 (2.09%)	6
Pulmonary fibrosis † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Pulmonary mass † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Respiratory failure † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	1/287 (0.35%)	1
Respiratory tract haemorrhage † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Upper airway obstruction † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Skin and subcutaneous tissue disorders
Erythema multiforme † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Pruritus † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Psoriasis † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Rash generalised † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Skin necrosis † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
Skin ulcer † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Swelling face † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Vascular disorders
Circulatory collapse † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Deep vein thrombosis † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	1/287 (0.35%)	1
Embolism † 1	0/300 (0.00%)	0	1/276 (0.36%)	1	0/287 (0.00%)	0
Haemorrhage † 1	1/300 (0.33%)	1	2/276 (0.72%)	2	0/287 (0.00%)	0
Hypotension † 1	2/300 (0.67%)	2	4/276 (1.45%)	4	4/287 (1.39%)	4
Neurogenic shock † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Thrombophlebitis † 1	0/300 (0.00%)	0	0/276 (0.00%)	0	1/287 (0.35%)	1
Venous thrombosis † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	0/287 (0.00%)	0
1 Term from vocabulary, MedDRA 21.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pembrolizumab Monotherapy (Pembro Mono)		Pembrolizumab + Chemotherapy (Pembro Combo)		Cetuximab + Chemotherapy (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	263/300 (87.67%)		265/276 (96.01%)		278/287 (96.86%)
Blood and lymphatic system disorders
Anaemia † 1	61/300 (20.33%)	82	153/276 (55.43%)	210	128/287 (44.60%)	239
Leukopenia † 1	4/300 (1.33%)	7	37/276 (13.41%)	57	41/287 (14.29%)	87
Lymphopenia † 1	7/300 (2.33%)	10	9/276 (3.26%)	20	16/287 (5.57%)	37
Neutropenia † 1	6/300 (2.00%)	14	90/276 (32.61%)	135	93/287 (32.40%)	195
Thrombocytopenia † 1	6/300 (2.00%)	7	74/276 (26.81%)	114	71/287 (24.74%)	149
Ear and labyrinth disorders
Tinnitus † 1	1/300 (0.33%)	1	17/276 (6.16%)	17	18/287 (6.27%)	20
Endocrine disorders
Hypothyroidism † 1	55/300 (18.33%)	59	44/276 (15.94%)	48	18/287 (6.27%)	21
Gastrointestinal disorders
Abdominal pain † 1	2/300 (0.67%)	2	9/276 (3.26%)	11	19/287 (6.62%)	27
Abdominal pain upper † 1	7/300 (2.33%)	7	11/276 (3.99%)	13	19/287 (6.62%)	24
Constipation † 1	59/300 (19.67%)	62	101/276 (36.59%)	145	95/287 (33.10%)	134
Diarrhoea † 1	44/300 (14.67%)	54	77/276 (27.90%)	121	96/287 (33.45%)	192
Dry mouth † 1	17/300 (5.67%)	18	21/276 (7.61%)	24	10/287 (3.48%)	12
Dyspepsia † 1	10/300 (3.33%)	11	15/276 (5.43%)	18	24/287 (8.36%)	28
Dysphagia † 1	20/300 (6.67%)	21	31/276 (11.23%)	38	27/287 (9.41%)	28
Nausea † 1	49/300 (16.33%)	58	139/276 (50.36%)	271	146/287 (50.87%)	276
Oral pain † 1	7/300 (2.33%)	7	18/276 (6.52%)	18	14/287 (4.88%)	14
Stomatitis † 1	9/300 (3.00%)	9	68/276 (24.64%)	105	77/287 (26.83%)	123
Vomiting † 1	33/300 (11.00%)	43	90/276 (32.61%)	155	77/287 (26.83%)	123
General disorders
Asthenia † 1	16/300 (5.33%)	16	46/276 (16.67%)	75	43/287 (14.98%)	64
Fatigue † 1	81/300 (27.00%)	94	94/276 (34.06%)	133	101/287 (35.19%)	162
Malaise † 1	6/300 (2.00%)	6	21/276 (7.61%)	26	11/287 (3.83%)	13
Mucosal inflammation † 1	12/300 (4.00%)	15	80/276 (28.99%)	131	80/287 (27.87%)	137
Oedema peripheral † 1	12/300 (4.00%)	12	17/276 (6.16%)	18	18/287 (6.27%)	21
Pyrexia † 1	36/300 (12.00%)	41	41/276 (14.86%)	70	34/287 (11.85%)	43
Infections and infestations
Oral candidiasis † 1	4/300 (1.33%)	4	22/276 (7.97%)	24	17/287 (5.92%)	25
Paronychia † 1	1/300 (0.33%)	1	0/276 (0.00%)	0	37/287 (12.89%)	53
Pneumonia † 1	13/300 (4.33%)	16	14/276 (5.07%)	16	12/287 (4.18%)	12
Investigations
Alanine aminotransferase increased † 1	13/300 (4.33%)	19	19/276 (6.88%)	23	22/287 (7.67%)	26
Aspartate aminotransferase increased † 1	17/300 (5.67%)	22	20/276 (7.25%)	25	24/287 (8.36%)	34
Blood creatinine increased † 1	12/300 (4.00%)	20	37/276 (13.41%)	61	24/287 (8.36%)	50
Lymphocyte count decreased † 1	10/300 (3.33%)	16	15/276 (5.43%)	33	13/287 (4.53%)	34
Neutrophil count decreased † 1	1/300 (0.33%)	1	50/276 (18.12%)	85	55/287 (19.16%)	106
Platelet count decreased † 1	3/300 (1.00%)	4	53/276 (19.20%)	98	49/287 (17.07%)	80
Weight decreased † 1	42/300 (14.00%)	44	43/276 (15.58%)	50	59/287 (20.56%)	65
White blood cell count decreased † 1	4/300 (1.33%)	6	36/276 (13.04%)	76	46/287 (16.03%)	110
Metabolism and nutrition disorders
Decreased appetite † 1	44/300 (14.67%)	51	78/276 (28.26%)	104	81/287 (28.22%)	112
Dehydration † 1	8/300 (2.67%)	8	13/276 (4.71%)	13	16/287 (5.57%)	18
Hypercalcaemia † 1	12/300 (4.00%)	12	17/276 (6.16%)	23	8/287 (2.79%)	9
Hyperglycaemia † 1	19/300 (6.33%)	28	15/276 (5.43%)	23	23/287 (8.01%)	42
Hyperkalaemia † 1	8/300 (2.67%)	10	17/276 (6.16%)	25	18/287 (6.27%)	48
Hypoalbuminaemia † 1	10/300 (3.33%)	11	23/276 (8.33%)	31	15/287 (5.23%)	22
Hypocalcaemia † 1	2/300 (0.67%)	2	17/276 (6.16%)	23	22/287 (7.67%)	49
Hypokalaemia † 1	23/300 (7.67%)	28	30/276 (10.87%)	43	53/287 (18.47%)	90
Hypomagnesaemia † 1	12/300 (4.00%)	12	42/276 (15.22%)	62	115/287 (40.07%)	268
Hyponatraemia † 1	26/300 (8.67%)	31	34/276 (12.32%)	53	36/287 (12.54%)	70
Hypophosphataemia † 1	8/300 (2.67%)	10	12/276 (4.35%)	18	26/287 (9.06%)	45
Musculoskeletal and connective tissue disorders
Arthralgia † 1	16/300 (5.33%)	20	15/276 (5.43%)	22	7/287 (2.44%)	9
Back pain † 1	21/300 (7.00%)	22	12/276 (4.35%)	15	11/287 (3.83%)	12
Neck pain † 1	18/300 (6.00%)	22	28/276 (10.14%)	30	20/287 (6.97%)	24
Nervous system disorders
Dizziness † 1	14/300 (4.67%)	16	28/276 (10.14%)	34	38/287 (13.24%)	62
Dysgeusia † 1	10/300 (3.33%)	10	19/276 (6.88%)	20	20/287 (6.97%)	23
Headache † 1	36/300 (12.00%)	42	32/276 (11.59%)	39	24/287 (8.36%)	36
Neuropathy peripheral † 1	1/300 (0.33%)	1	16/276 (5.80%)	18	8/287 (2.79%)	10
Peripheral sensory neuropathy † 1	2/300 (0.67%)	2	16/276 (5.80%)	17	7/287 (2.44%)	9
Psychiatric disorders
Anxiety † 1	15/300 (5.00%)	15	11/276 (3.99%)	12	15/287 (5.23%)	18
Insomnia † 1	21/300 (7.00%)	23	28/276 (10.14%)	31	24/287 (8.36%)	30
Respiratory, thoracic and mediastinal disorders
Cough † 1	40/300 (13.33%)	48	53/276 (19.20%)	65	37/287 (12.89%)	54
Dyspnoea † 1	35/300 (11.67%)	43	19/276 (6.88%)	20	18/287 (6.27%)	27
Epistaxis † 1	5/300 (1.67%)	6	9/276 (3.26%)	11	22/287 (7.67%)	34
Oropharyngeal pain † 1	9/300 (3.00%)	9	14/276 (5.07%)	15	20/287 (6.97%)	23
Productive cough † 1	17/300 (5.67%)	20	11/276 (3.99%)	11	6/287 (2.09%)	6
Skin and subcutaneous tissue disorders
Alopecia † 1	1/300 (0.33%)	1	15/276 (5.43%)	15	15/287 (5.23%)	15
Dermatitis acneiform † 1	8/300 (2.67%)	9	1/276 (0.36%)	1	83/287 (28.92%)	129
Dry skin † 1	13/300 (4.33%)	16	10/276 (3.62%)	11	37/287 (12.89%)	48
Palmar-plantar erythrodysaesthesia syndrome † 1	2/300 (0.67%)	2	4/276 (1.45%)	6	22/287 (7.67%)	31
Pruritus † 1	32/300 (10.67%)	39	24/276 (8.70%)	26	30/287 (10.45%)	49
Rash † 1	30/300 (10.00%)	42	29/276 (10.51%)	34	111/287 (38.68%)	159
Rash maculo-papular † 1	9/300 (3.00%)	9	9/276 (3.26%)	10	16/287 (5.57%)	24
Skin fissures † 1	0/300 (0.00%)	0	2/276 (0.72%)	3	38/287 (13.24%)	50
Vascular disorders
Hypertension † 1	13/300 (4.33%)	14	17/276 (6.16%)	26	15/287 (5.23%)	18
Hypotension † 1	6/300 (2.00%)	8	10/276 (3.62%)	11	20/287 (6.97%)	32
1 Term from vocabulary, MedDRA 21.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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

Results Point of Contact

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Takahashi S, Oridate N, Tanaka K, Shimizu Y, Fujimoto Y, Matsumoto K, Yokota T, Yamazaki T, Takahashi M, Ueda T, Hanai N, Yamaguchi H, Hara H, Yoshizaki T, Yasumatsu R, Nakayama M, Shiga K, Fujii T, Mitsugi K, Takahashi K, Nohata N, Gumuscu B, Swaby RF, Tahara M. First-line pembrolizumab +/- chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048. Int J Clin Oncol. 2022 Dec;27(12):1805-1817. doi: 10.1007/s10147-022-02233-6. Epub 2022 Oct 20.

Harrington KJ, Burtness B, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Lin J, Gumuscu B, Swaby RF, Rischin D. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol. 2023 Feb 1;41(4):790-802. doi: 10.1200/JCO.21.02508. Epub 2022 Oct 11.

Rischin D, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Ishak WZW, Hong RL, Mendoza RG, Jia L, Chirovsky D, Norquist J, Jin F, Burtness B. Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048. Oral Oncol. 2022 May;128:105815. doi: 10.1016/j.oraloncology.2022.105815. Epub 2022 Apr 2.

Burtness B, Rischin D, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Ge J, Swaby RF, Gumuscu B, Harrington K. Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. J Clin Oncol. 2022 Jul 20;40(21):2321-2332. doi: 10.1200/JCO.21.02198. Epub 2022 Mar 25.

Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, Gonzalez Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. doi: 10.1016/S0140-6736(19)32591-7. Epub 2019 Nov 1. Erratum In: Lancet. 2020 Jan 25;395(10220):272. Lancet. 2020 Feb 22;395(10224):564. Lancet. 2021 Jun 12;397(10291):2252.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02358031
• Other Study ID Numbers: 3475-048; MK-3475-048 ( Other Identifier: Merck Protocol Number ); KEYNOTE-048 ( Other Identifier: Merck ); 2014-003698-41 ( EudraCT Number )
• First Submitted: February 3, 2015
• First Posted: February 6, 2015
• Results First Submitted: January 29, 2020
• Results First Posted: February 17, 2020
• Last Update Posted: February 12, 2024