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)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02358031
• Collaborator: (none)
• Enrollment: 882
• Arms: 3
• Anticipated Duration (Months): 96.9

Study Details

Study Description

Brief Summary

Participants with recurrent or metastatic (R/M) squamous cell cancer of the head and neck (HNSCC) will be randomly assigned to receive pembrolizumab monotherapy [pembro mono], pembrolizumab plus chemotherapy with a platinum-based drug (cisplatin or carboplatin) and 5-Fluorouracil (5-FU) [pembro combo], or cetuximab plus a platinum-based drug (cisplatin or carboplatin) and 5-FU [control]. The overall primary study hypotheses are as follows in all participants and in participants with Programmed Cell Death Ligand 1 (PD-L1) positive expression defined by Combined Positive Score (CPS) ≥1 and CPS ≥20: 1) pembrolizumab monotherapy prolongs progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) assessed by Blinded Independent Central Review (BICR) and prolongs overall survival (OS) compared to standard treatment, and 2) pembrolizumab combination with chemotherapy prolongs PFS per RECIST 1.1 assessed by BICR and prolongs OS compared to standard treatment.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Head and Neck Cancer; Metastatic Head and Neck Cancer	Biological: Pembrolizumab; Drug: Cisplatin; Drug: Carboplatin; Drug: 5-FU; Biological: Cetuximab	Phase 3

Detailed Description

The 12 primary superiority hypotheses will be evaluated by comparing the pembro mono arm or pembro combo arm separately to the control arm, for PFS and OS in all first line (1L) R/M HNSCC participants and in 1L R/M HNSCC participants with positive PD-L1 expression (PD-L1 CPS ≥1 and CPS ≥20).

Study Design

• Study Type: Interventional
• Actual Enrollment: 882 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Clinical Trial of Pembrolizumab (MK-3475) in First Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
• Actual Study Start Date: Mar 19, 2015
• Actual Primary Completion Date: Feb 25, 2019
• Anticipated Study Completion Date: Apr 14, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab Monotherapy (Pembro Mono) Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 24 months.	Biological: Pembrolizumab; Pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months.; Other Names: KEYTRUDA® MK-3475
Experimental: Pembrolizumab + Chemotherapy (Pembro Combo) Participants receive 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).	Biological: Pembrolizumab; Pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 24 months.; Other Names: KEYTRUDA® MK-3475 ; Drug: Cisplatin; Cisplatin 100 mg/m^2 IV on Day 1 of each 3-week cycle (6 cycle maximum).; Drug: Carboplatin; Carboplatin at a target AUC 5 IV on Day 1 of each 3-week cycle (6 cycle maximum).; Drug: 5-FU; 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).
Active Comparator: Cetuximab + Chemotherapy (Control) Participants receive 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).	Drug: Cisplatin; Cisplatin 100 mg/m^2 IV on Day 1 of each 3-week cycle (6 cycle maximum).; Drug: Carboplatin; Carboplatin at a target AUC 5 IV on Day 1 of each 3-week cycle (6 cycle maximum).; Drug: 5-FU; 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum).; Biological: Cetuximab; 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

Outcome Measures

Primary Outcome Measures

1. 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 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

2. 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 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

3. Pembro Combo vs Control: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

4. Pembro Combo vs Control: Overall Survival (OS) in All Participants [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

5. Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥1 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

6. Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥20 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

7. Pembro Mono vs Control: PFS Per RECIST 1.1 by BICR in All Participants [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

8. Pembro Mono vs Control: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

9. Pembro Mono vs Control: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

10. Pembro Mono vs Control: OS in All Participants [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

    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.

11. Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥1 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

    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.

12. Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥20 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

    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.

Secondary Outcome Measures

1. Pembro Combo vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among All Participants [Month 6]

   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.

2. 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 [Month 6]

   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.

3. 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 [Month 6]

   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.

4. Pembro Combo vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among All Participants [Month 12]

   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.

5. 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 [Month 12]

   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.

6. 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 [Month 12]

   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.

7. Pembro Combo vs Control: Objective Response Rate (ORR) Per RECIST 1.1 by BICR in All Participants [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

8. Pembro Combo vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

9. Pembro Combo vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

   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.

10. 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 [Baseline, Week 15]

    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.

11. 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) [Baseline up to approximately 12 months]

    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.

12. Pembro Combo vs Control: TTD in the EORTC QLQ- Head and Neck Module 35 (H&N35) Pain Score (Kaplan-Meier Method) [Baseline up to approximately 12 months]

    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.

13. Pembro Combo vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score (Kaplan-Meier Method) [Baseline up to approximately 12 months]

    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.

14. Pembro Mono vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among All Participants [Month 6]

    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.

15. 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 [Month 6]

    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.

16. 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 [Month 6]

    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.

17. Pembro Mono vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among All Participants [Month 12]

    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.

18. 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 [Month 12]

    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.

19. 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 [Month 12]

    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.

20. Pembro Mono vs Control: ORR Per RECIST 1.1 by BICR in All Participants [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

    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.

21. Pembro Mono vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

    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.

22. Pembro Mono vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20 [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

    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.

23. 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 [Baseline, Week 15]

    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.

24. Pembro Mono vs Control: TTD in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score [Baseline up to approximately 12 months]

    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.

25. Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Pain Score [Baseline up to approximately 12 months]

    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.

26. Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score [Baseline up to approximately 12 months]

    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.

27. Number of Participants Experiencing an Adverse Event (AE) [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

    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.

28. Number of Participants Who Discontinued Study Drug Due to an AE [Up to approximately 47 months (through Final Analysis cut-off date of 25-Feb-2019)]

    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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically- or cytologically-confirmed recurrent or metastatic head and neck squamous cell carcinoma considered incurable by local therapies

• No prior systemic therapy administered in the recurrent or metastatic setting (with the exception of systemic therapy completed > 6 months prior if given as part of multimodal treatment for locally advanced disease)

• Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. Participants may not have a primary tumor site of nasopharynx (any histology)

• Measurable disease

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Adequate organ function

• Can provide tissue for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate is not sufficient): A newly obtained biopsy (within 90 days prior to start of study treatment) is preferred but an archival sample is acceptable.

• Have results from testing of human papillomavirus (HPV) status for oropharyngeal cancer

• Female participants of childbearing potential should have a negative pregnancy test and must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study medication

• Male participants must agree to use an adequate method of contraception starting with the first dose of study medication through 180 days after the last dose of study medication

Exclusion Criteria:

• Disease suitable for local therapy administered with curative intent

• Has progressive disease (PD) within six (6) months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC

• Radiation therapy (or other non-systemic therapy) within 2 weeks prior to randomization or not fully recovered from adverse events due to a previously administered treatment

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

• Life expectancy of <3 months and/or has rapidly progressing disease

• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication (physiologic doses of corticosteroids may be approved after consultation with the Sponsor)

• Diagnosed and/or treated additional malignancy within 5 years prior to randomization with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers

• Has had an allogeneic tissue/solid organ transplant

• Active central nervous system metastases and/or carcinomatous meningitis

• Active autoimmune disease that has required systemic treatment in past 2 years; replacement therapy is not considered a form of systemic treatment

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

• Active infection requiring systemic therapy

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

• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of study medication

• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or previously participated in Merck MK-3475 clinical trial

• Known history of human immunodeficiency virus (HIV)

• Known active Hepatitis B or C

• Received a live vaccine within 30 days of planned start of study medication

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 11, 2019

More Information

Additional Information:

• Merck Oncology Clinical Trials Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02358031
• Other Study ID Numbers: 3475-048; MK-3475-048; KEYNOTE-048; 2014-003698-41
• First Posted: Feb 6, 2015
• Last Update Posted: Aug 19, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Merck Sharp & Dohme LLC: Programmed Cell Death-1 (PD1, PD-1),; Programmed Cell Death Receptor Ligand 1 (PDL1, PD-L1); Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2); chemotherapy, 5-fluorouracil, cisplatin, carboplatin
• Additional relevant MeSH terms: Head and Neck Neoplasms; Recurrence; Carboplatin; Pembrolizumab; Cetuximab

Study Results

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 Detail	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

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 Participants	301	281	300	882
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.2 (9.4)	60.7 (9.8)	61.0 (10.0)	61.0 (9.7)
Sex: Female, Male (Count of Participants)
Female	51 16.9%	57 20.3%	39 13%	147 16.7%
Male	250 83.1%	224 79.7%	261 87%	735 83.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	46 15.3%	45 16%	44 14.7%	135 15.3%
Not Hispanic or Latino	233 77.4%	213 75.8%	231 77%	677 76.8%
Unknown or Not Reported	22 7.3%	23 8.2%	25 8.3%	70 7.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	5 1.7%	3 1.1%	6 2%	14 1.6%
Asian	58 19.3%	60 21.4%	54 18%	172 19.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	4 1.3%	11 3.9%	6 2%	21 2.4%
White	219 72.8%	203 72.2%	224 74.7%	646 73.2%
More than one race	12 4%	4 1.4%	9 3%	25 2.8%
Unknown or Not Reported	3 1%	0 0%	1 0.3%	4 0.5%
Eastern Cooperative Group (ECOG) Performance Status (Count of Participants)
ECOG = 0	118 39.2%	110 39.1%	117 39%	345 39.1%
ECOG = 1	183 60.8%	171 60.9%	183 61%	537 60.9%
Human Papillomavirus (HPV) Status (Count of 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%
PD-L1 TPS Status (Count of Participants)
Strongly Positive	67 22.3%	66 23.5%	66 22%	199 22.6%
Not Strongly Positive	234 77.7%	215 76.5%	234 78%	683 77.4%
PD-L1 CPS ≥1 Status (Count of Participants)
CPS<1	44 14.6%	39 13.9%	45 15%	128 14.5%
CPS ≥1	257 85.4%	242 86.1%	255 85%	754 85.5%
PD-L1 CPS ≥20 Status (Count of 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%	5 0.6%

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).
Measure Participants	0	281	278
Median (95% Confidence Interval) [Months]	4.9	5.2

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	242	235
Median (95% Confidence Interval) [Months]	5.1	5.0

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	126	110
Median (95% Confidence Interval) [Months]	5.8	5.3

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	281	278
Median (95% Confidence Interval) [Months]	13.0	10.7

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	242	235
Median (95% Confidence Interval) [Months]	13.6	10.4

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	126	110
Median (95% Confidence Interval) [Months]	14.7	11.0

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	301	0	300
Median (95% Confidence Interval) [Months]	2.3	5.2

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 1.09 to 1.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	257	0	255
Median (95% Confidence Interval) [Months]	3.2	5.0

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.94 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	133	0	122
Median (95% Confidence Interval) [Months]	3.4	5.3

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	301	0	300
Median (95% Confidence Interval) [Months]	11.5	10.7

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.70 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	257	0	255
Median (95% Confidence Interval) [Months]	12.3	10.3

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.61 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	133	0	122
Median (95% Confidence Interval) [Months]	14.8	10.7

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	281	278
Number (95% Confidence Interval) [Percentage of Participants]	44.7 14.9%	44.9 16%

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).
Measure Participants	0	242	235
Number (95% Confidence Interval) [Percentage of Participants]	44.9 14.9%	43.3 15.4%

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).
Measure Participants	0	126	110
Number (95% Confidence Interval) [Percentage of Participants]	49.4 16.4%	47.2 16.8%

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).
Measure Participants	0	281	278
Number (95% Confidence Interval) [Percentage of Participants]	17.2 5.7%	13.6 4.8%

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).
Measure Participants	0	242	235
Number (95% Confidence Interval) [Percentage of Participants]	19.7 6.5%	12.5 4.4%

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).
Measure Participants	0	126	110
Number (95% Confidence Interval) [Percentage of Participants]	23.9 7.9%	14.0 5%

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).
Measure Participants	0	281	278
Number (95% Confidence Interval) [Percentage of Participants]	35.6 11.8%	36.3 12.9%

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
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
Method of Estimation	Estimation Parameter	Difference in ORR Percentage
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -8.7 to 7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	242	235
Number (95% Confidence Interval) [Percentage of Participants]	36.4 12.1%	35.7 12.7%

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
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
Method of Estimation	Estimation Parameter	Difference in ORR Percentage
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -8.2 to 9.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	126	110
Number (95% Confidence Interval) [Percentage of Participants]	42.9 14.3%	38.2 13.6%

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
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
Method of Estimation	Estimation Parameter	Difference in ORR Percentage
	Estimated Value	5.0
	Confidence Interval	(2-Sided) 95%; -7.5 to 17.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	268	259
Least Squares Mean (95% Confidence Interval) [Score on a Scale]	1.17	0.77

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
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
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; -3.46 to 4.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	270	260
Median (95% Confidence Interval) [Months]	NA	NA

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.94 to 2.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	268	260
Median (95% Confidence Interval) [Months]	NA	NA

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.93 to 2.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	0	268	260
Median (95% Confidence Interval) [Months]	NA	NA

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	301	0	300
Number (95% Confidence Interval) [Percentage of Participants]	26.2 8.7%	45.7 16.3%

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).
Measure Participants	257	0	255
Number (95% Confidence Interval) [Percentage of Participants]	28.7 9.5%	43.9 15.6%

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).
Measure Participants	133	0	122
Number (95% Confidence Interval) [Percentage of Participants]	33.0 11%	46.6 16.6%

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).
Measure Participants	301	0	300
Number (95% Confidence Interval) [Percentage of Participants]	17.6 5.8%	15.0 5.3%

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).
Measure Participants	257	0	255
Number (95% Confidence Interval) [Percentage of Participants]	20.6 6.8%	13.6 4.8%

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).
Measure Participants	133	0	122
Number (95% Confidence Interval) [Percentage of Participants]	23.5 7.8%	15.1 5.4%

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).
Measure Participants	301	0	300
Number (95% Confidence Interval) [Percentage of Participants]	16.9 5.6%	36.0 12.8%

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
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
Method of Estimation	Estimation Parameter	Difference in ORR Percentage
	Estimated Value	-19.0
	Confidence Interval	(2-Sided) 95%; -25.8 to -12.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	257	0	255
Number (95% Confidence Interval) [Percentage of Participants]	19.1 6.3%	34.9 12.4%

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
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
Method of Estimation	Estimation Parameter	Difference in ORR Percentage
	Estimated Value	-15.9
	Confidence Interval	(2-Sided) 95%; -23.4 to -8.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	133	0	122
Number (95% Confidence Interval) [Percentage of Participants]	23.3 7.7%	36.1 12.8%

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
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
Method of Estimation	Estimation Parameter	Difference in ORR Percentage
	Estimated Value	-12.8
	Confidence Interval	(2-Sided) 95%; -23.8 to -1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	294	0	279
Least Squares Mean (95% Confidence Interval) [Score on a Scale]	0.85	0.60

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
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
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; -3.34 to 3.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	294	0	280
Median (95% Confidence Interval) [Months]	NA	NA

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 95%; 0.95 to 2.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	295	0	280
Median (95% Confidence Interval) [Months]	NA	NA

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	295	0	280
Median (95% Confidence Interval) [Months]	NA	NA

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
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	300	276	287
Count of Participants [Participants]	290 96.3%	271 96.4%	286 95.3%

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).
Measure Participants	300	276	287
Count of Participants [Participants]	36 12%	90 32%	79 26.3%

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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	237/301 (78.7%)		214/281 (76.2%)		265/300 (88.3%)
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%)		165/276 (59.8%)		141/287 (49.1%)
Blood and lymphatic system disorders
Anaemia	1/300 (0.3%)	1	14/276 (5.1%)	17	9/287 (3.1%)	11
Anaemia of chronic disease	0/300 (0%)	0	1/276 (0.4%)	2	0/287 (0%)	0
Disseminated intravascular coagulation	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Febrile neutropenia	0/300 (0%)	0	17/276 (6.2%)	17	15/287 (5.2%)	16
Haematotoxicity	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Leukopenia	0/300 (0%)	0	1/276 (0.4%)	1	1/287 (0.3%)	1
Lymphadenitis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Neutropenia	0/300 (0%)	0	6/276 (2.2%)	6	4/287 (1.4%)	6
Pancytopenia	0/300 (0%)	0	1/276 (0.4%)	1	1/287 (0.3%)	1
Thrombocytopenia	0/300 (0%)	0	6/276 (2.2%)	6	0/287 (0%)	0
Cardiac disorders
Acute myocardial infarction	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Angina pectoris	1/300 (0.3%)	1	1/276 (0.4%)	1	0/287 (0%)	0
Atrial fibrillation	1/300 (0.3%)	1	1/276 (0.4%)	1	3/287 (1%)	3
Autoimmune myocarditis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Cardiac arrest	0/300 (0%)	0	2/276 (0.7%)	2	0/287 (0%)	0
Cardiac failure	0/300 (0%)	0	2/276 (0.7%)	2	0/287 (0%)	0
Cardiac failure acute	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Cardiopulmonary failure	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Myocardial infarction	3/300 (1%)	3	3/276 (1.1%)	3	3/287 (1%)	3
Myocardial ischaemia	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Palpitations	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Supraventricular extrasystoles	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Supraventricular tachycardia	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Tachycardia	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Endocrine disorders
Adrenal insufficiency	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Hypercalcaemia of malignancy	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Hyperthyroidism	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Hypophysitis	0/300 (0%)	0	1/276 (0.4%)	2	0/287 (0%)	0
Hypopituitarism	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/300 (0.3%)	1	2/276 (0.7%)	2	1/287 (0.3%)	1
Abdominal pain upper	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Colitis	0/300 (0%)	0	1/276 (0.4%)	1	2/287 (0.7%)	2
Colitis microscopic	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Constipation	2/300 (0.7%)	2	1/276 (0.4%)	1	0/287 (0%)	0
Diarrhoea	2/300 (0.7%)	2	1/276 (0.4%)	1	4/287 (1.4%)	4
Duodenal ulcer	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Dysphagia	4/300 (1.3%)	4	2/276 (0.7%)	2	1/287 (0.3%)	1
Enteritis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Enterocolitis	2/300 (0.7%)	2	0/276 (0%)	0	0/287 (0%)	0
Gastric haemorrhage	1/300 (0.3%)	1	1/276 (0.4%)	1	1/287 (0.3%)	1
Gastric perforation	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Gastric ulcer	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Gastritis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Gastrointestinal toxicity	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Haematemesis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Haematochezia	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Haemorrhoids	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Intestinal obstruction	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Intestinal perforation	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Lower gastrointestinal haemorrhage	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Mouth haemorrhage	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Nausea	0/300 (0%)	0	6/276 (2.2%)	6	8/287 (2.8%)	9
Oesophageal fistula	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Oral cavity fistula	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Pancreatitis acute	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Peptic ulcer haemorrhage	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Pneumatosis intestinalis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Pneumoperitoneum	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Stomatitis	0/300 (0%)	0	8/276 (2.9%)	8	4/287 (1.4%)	4
Tongue oedema	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Umbilical hernia	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Upper gastrointestinal haemorrhage	1/300 (0.3%)	1	0/276 (0%)	0	3/287 (1%)	3
Vomiting	0/300 (0%)	0	5/276 (1.8%)	5	5/287 (1.7%)	5
General disorders
Asthenia	1/300 (0.3%)	1	0/276 (0%)	0	2/287 (0.7%)	2
Catheter site inflammation	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Chest pain	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Complication associated with device	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Death	2/300 (0.7%)	2	2/276 (0.7%)	2	2/287 (0.7%)	2
Fatigue	3/300 (1%)	3	1/276 (0.4%)	1	3/287 (1%)	3
General physical health deterioration	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Hyperthermia	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Localised oedema	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Mucosal inflammation	1/300 (0.3%)	1	6/276 (2.2%)	6	1/287 (0.3%)	1
Multiple organ dysfunction syndrome	2/300 (0.7%)	2	2/276 (0.7%)	2	0/287 (0%)	0
Peripheral swelling	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Pneumatosis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Pyrexia	2/300 (0.7%)	2	7/276 (2.5%)	7	1/287 (0.3%)	1
Sudden death	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Swelling	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Hepatobiliary disorders
Autoimmune hepatitis	2/300 (0.7%)	2	1/276 (0.4%)	1	0/287 (0%)	0
Cholecystitis acute	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Immune system disorders
Anaphylactic reaction	1/300 (0.3%)	1	0/276 (0%)	0	2/287 (0.7%)	2
Autoinflammatory disease	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Hypersensitivity	1/300 (0.3%)	1	1/276 (0.4%)	1	1/287 (0.3%)	1
Type III immune complex mediated reaction	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Infections and infestations
Abdominal infection	0/300 (0%)	0	0/276 (0%)	0	2/287 (0.7%)	2
Abscess limb	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Abscess neck	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Arthritis bacterial	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Atypical pneumonia	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Bacteraemia	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Bronchitis	2/300 (0.7%)	2	3/276 (1.1%)	4	2/287 (0.7%)	2
Cellulitis	2/300 (0.7%)	2	2/276 (0.7%)	2	1/287 (0.3%)	2
Cytomegalovirus gastrointestinal infection	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Device related infection	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Device related sepsis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Encephalitis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Epidural empyema	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Escherichia bacteraemia	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Escherichia infection	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Gastroenteritis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Gastroenteritis norovirus	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Gastrointestinal viral infection	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Herpes zoster	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Infection	1/300 (0.3%)	1	1/276 (0.4%)	1	1/287 (0.3%)	1
Infective exacerbation of chronic obstructive airways disease	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Influenza	0/300 (0%)	0	1/276 (0.4%)	1	1/287 (0.3%)	1
Klebsiella sepsis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Laryngitis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Lower respiratory tract infection	0/300 (0%)	0	1/276 (0.4%)	1	1/287 (0.3%)	1
Lung infection	3/300 (1%)	5	7/276 (2.5%)	7	2/287 (0.7%)	2
Lung infection pseudomonal	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Medical device site abscess	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Medical device site infection	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Neutropenic sepsis	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Oral candidiasis	2/300 (0.7%)	2	0/276 (0%)	0	0/287 (0%)	0
Osteomyelitis	0/300 (0%)	0	0/276 (0%)	0	2/287 (0.7%)	2
Otitis media	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Penile infection	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Peritonitis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Pneumonia	18/300 (6%)	20	16/276 (5.8%)	18	18/287 (6.3%)	22
Pneumonia bacterial	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Pneumonia staphylococcal	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Pseudomonal sepsis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Pulmonary sepsis	1/300 (0.3%)	1	1/276 (0.4%)	1	0/287 (0%)	0
Respiratory tract infection	1/300 (0.3%)	1	4/276 (1.4%)	5	1/287 (0.3%)	1
Sepsis	6/300 (2%)	6	4/276 (1.4%)	4	2/287 (0.7%)	2
Septic shock	1/300 (0.3%)	1	6/276 (2.2%)	6	2/287 (0.7%)	2
Skin infection	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Soft tissue infection	3/300 (1%)	4	0/276 (0%)	0	1/287 (0.3%)	1
Staphylococcal infection	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Staphylococcal sepsis	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Stoma site infection	1/300 (0.3%)	1	1/276 (0.4%)	1	2/287 (0.7%)	2
Tracheitis	1/300 (0.3%)	2	2/276 (0.7%)	2	0/287 (0%)	0
Tracheobronchitis	1/300 (0.3%)	1	1/276 (0.4%)	1	0/287 (0%)	0
Tracheostomy infection	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Upper respiratory tract infection	0/300 (0%)	0	1/276 (0.4%)	1	1/287 (0.3%)	1
Urinary tract infection	0/300 (0%)	0	1/276 (0.4%)	1	3/287 (1%)	3
Vascular device infection	2/300 (0.7%)	2	1/276 (0.4%)	1	3/287 (1%)	3
Viral infection	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Wound infection	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Wound sepsis	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Injury, poisoning and procedural complications
Alcohol poisoning	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Ankle fracture	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Arterial injury	1/300 (0.3%)	1	1/276 (0.4%)	1	0/287 (0%)	0
Contusion	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Fall	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Femur fracture	0/300 (0%)	0	0/276 (0%)	0	2/287 (0.7%)	2
Gastrointestinal stoma complication	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Gastrostomy failure	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Head injury	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Heat stroke	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Hip fracture	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Infusion related reaction	0/300 (0%)	0	1/276 (0.4%)	1	3/287 (1%)	3
Osteoradionecrosis	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Post procedural haemorrhage	1/300 (0.3%)	1	1/276 (0.4%)	1	0/287 (0%)	0
Spinal compression fracture	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Stoma site extravasation	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Stoma site pain	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Synovial rupture	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Tibia fracture	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Tracheal obstruction	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Tracheostomy malfunction	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Traumatic fracture	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	2
Investigations
Alanine aminotransferase increased	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Aspartate aminotransferase increased	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Blood calcium increased	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Blood creatinine increased	0/300 (0%)	0	3/276 (1.1%)	3	0/287 (0%)	0
Blood potassium decreased	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
C-reactive protein increased	1/300 (0.3%)	2	0/276 (0%)	0	0/287 (0%)	0
Glomerular filtration rate decreased	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Neutrophil count decreased	0/300 (0%)	0	0/276 (0%)	0	3/287 (1%)	3
Platelet count decreased	0/300 (0%)	0	3/276 (1.1%)	3	1/287 (0.3%)	1
Transaminases increased	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Weight decreased	2/300 (0.7%)	2	1/276 (0.4%)	1	1/287 (0.3%)	1
White blood cell count decreased	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Metabolism and nutrition disorders
Decreased appetite	1/300 (0.3%)	1	5/276 (1.8%)	7	4/287 (1.4%)	4
Dehydration	1/300 (0.3%)	1	6/276 (2.2%)	6	4/287 (1.4%)	4
Electrolyte imbalance	1/300 (0.3%)	1	1/276 (0.4%)	1	0/287 (0%)	0
Hypercalcaemia	4/300 (1.3%)	4	3/276 (1.1%)	3	2/287 (0.7%)	2
Hyperglycaemia	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Hyperglycaemic hyperosmolar nonketotic syndrome	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Hyperkalaemia	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	2
Hyperuricaemia	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Hypocalcaemia	0/300 (0%)	0	1/276 (0.4%)	1	1/287 (0.3%)	1
Hypokalaemia	1/300 (0.3%)	1	4/276 (1.4%)	4	1/287 (0.3%)	1
Hypomagnesaemia	0/300 (0%)	0	2/276 (0.7%)	2	1/287 (0.3%)	1
Hyponatraemia	1/300 (0.3%)	1	7/276 (2.5%)	7	2/287 (0.7%)	2
Malnutrition	2/300 (0.7%)	2	0/276 (0%)	0	1/287 (0.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Arthritis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Arthropathy	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Fistula	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Joint swelling	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Neck pain	1/300 (0.3%)	2	0/276 (0%)	0	1/287 (0.3%)	1
Polyarthritis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Rhabdomyolysis	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Synovial cyst	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Cancer pain	2/300 (0.7%)	2	1/276 (0.4%)	1	1/287 (0.3%)	1
Haemorrhagic tumour necrosis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Infected neoplasm	3/300 (1%)	3	1/276 (0.4%)	1	2/287 (0.7%)	2
Metastases to bone	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Prostate cancer	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Squamous cell carcinoma of the oral cavity	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Tumour flare	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Tumour haemorrhage	11/300 (3.7%)	13	6/276 (2.2%)	7	5/287 (1.7%)	5
Tumour pain	1/300 (0.3%)	1	1/276 (0.4%)	1	0/287 (0%)	0
Nervous system disorders
Carotid artery perforation	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Carotid sinus syndrome	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Cauda equina syndrome	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Cerebral infarction	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Cerebral ischaemia	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Cerebrovascular accident	0/300 (0%)	0	0/276 (0%)	0	2/287 (0.7%)	2
Embolic stroke	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Hemiparesis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Ischaemic stroke	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Presyncope	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Restless legs syndrome	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Seizure	1/300 (0.3%)	1	1/276 (0.4%)	1	1/287 (0.3%)	1
Spinal cord compression	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Syncope	0/300 (0%)	0	2/276 (0.7%)	2	5/287 (1.7%)	5
Toxic encephalopathy	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Vocal cord paralysis	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Product Issues
Device dislocation	0/300 (0%)	0	2/276 (0.7%)	2	1/287 (0.3%)	1
Device leakage	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Device occlusion	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Stent malfunction	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Psychiatric disorders
Anxiety	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Completed suicide	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Delirium	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Stress	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Suicide attempt	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Renal and urinary disorders
Acute kidney injury	4/300 (1.3%)	4	5/276 (1.8%)	5	1/287 (0.3%)	1
Renal failure	0/300 (0%)	0	3/276 (1.1%)	3	2/287 (0.7%)	2
Renal impairment	0/300 (0%)	0	1/276 (0.4%)	2	0/287 (0%)	0
Renal tubular necrosis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Tubulointerstitial nephritis	2/300 (0.7%)	2	0/276 (0%)	0	0/287 (0%)	0
Urinary retention	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Aspiration	2/300 (0.7%)	2	0/276 (0%)	0	0/287 (0%)	0
Bronchial obstruction	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Chronic obstructive pulmonary disease	1/300 (0.3%)	1	1/276 (0.4%)	1	0/287 (0%)	0
Dyspnoea	7/300 (2.3%)	9	2/276 (0.7%)	2	2/287 (0.7%)	2
Epistaxis	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Haemoptysis	1/300 (0.3%)	1	1/276 (0.4%)	1	0/287 (0%)	0
Hydrothorax	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Hypoxia	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Interstitial lung disease	1/300 (0.3%)	1	3/276 (1.1%)	3	1/287 (0.3%)	1
Laryngeal fistula	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Laryngeal obstruction	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Laryngeal oedema	1/300 (0.3%)	1	4/276 (1.4%)	5	1/287 (0.3%)	2
Lung infiltration	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Pharyngeal haemorrhage	1/300 (0.3%)	1	2/276 (0.7%)	2	0/287 (0%)	0
Pleural effusion	2/300 (0.7%)	2	3/276 (1.1%)	3	0/287 (0%)	0
Pneumonia aspiration	5/300 (1.7%)	5	8/276 (2.9%)	10	3/287 (1%)	3
Pneumonitis	3/300 (1%)	3	2/276 (0.7%)	2	1/287 (0.3%)	1
Pneumothorax	0/300 (0%)	0	1/276 (0.4%)	1	1/287 (0.3%)	1
Pulmonary artery thrombosis	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Pulmonary embolism	2/300 (0.7%)	2	4/276 (1.4%)	4	6/287 (2.1%)	6
Pulmonary fibrosis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Pulmonary mass	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Respiratory failure	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Respiratory tract haemorrhage	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Upper airway obstruction	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Skin and subcutaneous tissue disorders
Erythema multiforme	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Pruritus	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Psoriasis	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Rash generalised	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Skin necrosis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Skin ulcer	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Swelling face	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Vascular disorders
Circulatory collapse	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Deep vein thrombosis	1/300 (0.3%)	1	0/276 (0%)	0	1/287 (0.3%)	1
Embolism	0/300 (0%)	0	1/276 (0.4%)	1	0/287 (0%)	0
Haemorrhage	1/300 (0.3%)	1	2/276 (0.7%)	2	0/287 (0%)	0
Hypotension	2/300 (0.7%)	2	4/276 (1.4%)	4	4/287 (1.4%)	4
Neurogenic shock	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Thrombophlebitis	0/300 (0%)	0	0/276 (0%)	0	1/287 (0.3%)	1
Venous thrombosis	1/300 (0.3%)	1	0/276 (0%)	0	0/287 (0%)	0
Other (Not Including 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	263/300 (87.7%)		265/276 (96%)		278/287 (96.9%)
Blood and lymphatic system disorders
Anaemia	61/300 (20.3%)	82	153/276 (55.4%)	210	128/287 (44.6%)	239
Leukopenia	4/300 (1.3%)	7	37/276 (13.4%)	57	41/287 (14.3%)	87
Lymphopenia	7/300 (2.3%)	10	9/276 (3.3%)	20	16/287 (5.6%)	37
Neutropenia	6/300 (2%)	14	90/276 (32.6%)	135	93/287 (32.4%)	195
Thrombocytopenia	6/300 (2%)	7	74/276 (26.8%)	114	71/287 (24.7%)	149
Ear and labyrinth disorders
Tinnitus	1/300 (0.3%)	1	17/276 (6.2%)	17	18/287 (6.3%)	20
Endocrine disorders
Hypothyroidism	55/300 (18.3%)	59	44/276 (15.9%)	48	18/287 (6.3%)	21
Gastrointestinal disorders
Abdominal pain	2/300 (0.7%)	2	9/276 (3.3%)	11	19/287 (6.6%)	27
Abdominal pain upper	7/300 (2.3%)	7	11/276 (4%)	13	19/287 (6.6%)	24
Constipation	59/300 (19.7%)	62	101/276 (36.6%)	145	95/287 (33.1%)	134
Diarrhoea	44/300 (14.7%)	54	77/276 (27.9%)	121	96/287 (33.4%)	192
Dry mouth	17/300 (5.7%)	18	21/276 (7.6%)	24	10/287 (3.5%)	12
Dyspepsia	10/300 (3.3%)	11	15/276 (5.4%)	18	24/287 (8.4%)	28
Dysphagia	20/300 (6.7%)	21	31/276 (11.2%)	38	27/287 (9.4%)	28
Nausea	49/300 (16.3%)	58	139/276 (50.4%)	271	146/287 (50.9%)	276
Oral pain	7/300 (2.3%)	7	18/276 (6.5%)	18	14/287 (4.9%)	14
Stomatitis	9/300 (3%)	9	68/276 (24.6%)	105	77/287 (26.8%)	123
Vomiting	33/300 (11%)	43	90/276 (32.6%)	155	77/287 (26.8%)	123
General disorders
Asthenia	16/300 (5.3%)	16	46/276 (16.7%)	75	43/287 (15%)	64
Fatigue	81/300 (27%)	94	94/276 (34.1%)	133	101/287 (35.2%)	162
Malaise	6/300 (2%)	6	21/276 (7.6%)	26	11/287 (3.8%)	13
Mucosal inflammation	12/300 (4%)	15	80/276 (29%)	131	80/287 (27.9%)	137
Oedema peripheral	12/300 (4%)	12	17/276 (6.2%)	18	18/287 (6.3%)	21
Pyrexia	36/300 (12%)	41	41/276 (14.9%)	70	34/287 (11.8%)	43
Infections and infestations
Oral candidiasis	4/300 (1.3%)	4	22/276 (8%)	24	17/287 (5.9%)	25
Paronychia	1/300 (0.3%)	1	0/276 (0%)	0	37/287 (12.9%)	53
Pneumonia	13/300 (4.3%)	16	14/276 (5.1%)	16	12/287 (4.2%)	12
Investigations
Alanine aminotransferase increased	13/300 (4.3%)	19	19/276 (6.9%)	23	22/287 (7.7%)	26
Aspartate aminotransferase increased	17/300 (5.7%)	22	20/276 (7.2%)	25	24/287 (8.4%)	34
Blood creatinine increased	12/300 (4%)	20	37/276 (13.4%)	61	24/287 (8.4%)	50
Lymphocyte count decreased	10/300 (3.3%)	16	15/276 (5.4%)	33	13/287 (4.5%)	34
Neutrophil count decreased	1/300 (0.3%)	1	50/276 (18.1%)	85	55/287 (19.2%)	106
Platelet count decreased	3/300 (1%)	4	53/276 (19.2%)	98	49/287 (17.1%)	80
Weight decreased	42/300 (14%)	44	43/276 (15.6%)	50	59/287 (20.6%)	65
White blood cell count decreased	4/300 (1.3%)	6	36/276 (13%)	76	46/287 (16%)	110
Metabolism and nutrition disorders
Decreased appetite	44/300 (14.7%)	51	78/276 (28.3%)	104	81/287 (28.2%)	112
Dehydration	8/300 (2.7%)	8	13/276 (4.7%)	13	16/287 (5.6%)	18
Hypercalcaemia	12/300 (4%)	12	17/276 (6.2%)	23	8/287 (2.8%)	9
Hyperglycaemia	19/300 (6.3%)	28	15/276 (5.4%)	23	23/287 (8%)	42
Hyperkalaemia	8/300 (2.7%)	10	17/276 (6.2%)	25	18/287 (6.3%)	48
Hypoalbuminaemia	10/300 (3.3%)	11	23/276 (8.3%)	31	15/287 (5.2%)	22
Hypocalcaemia	2/300 (0.7%)	2	17/276 (6.2%)	23	22/287 (7.7%)	49
Hypokalaemia	23/300 (7.7%)	28	30/276 (10.9%)	43	53/287 (18.5%)	90
Hypomagnesaemia	12/300 (4%)	12	42/276 (15.2%)	62	115/287 (40.1%)	268
Hyponatraemia	26/300 (8.7%)	31	34/276 (12.3%)	53	36/287 (12.5%)	70
Hypophosphataemia	8/300 (2.7%)	10	12/276 (4.3%)	18	26/287 (9.1%)	45
Musculoskeletal and connective tissue disorders
Arthralgia	16/300 (5.3%)	20	15/276 (5.4%)	22	7/287 (2.4%)	9
Back pain	21/300 (7%)	22	12/276 (4.3%)	15	11/287 (3.8%)	12
Neck pain	18/300 (6%)	22	28/276 (10.1%)	30	20/287 (7%)	24
Nervous system disorders
Dizziness	14/300 (4.7%)	16	28/276 (10.1%)	34	38/287 (13.2%)	62
Dysgeusia	10/300 (3.3%)	10	19/276 (6.9%)	20	20/287 (7%)	23
Headache	36/300 (12%)	42	32/276 (11.6%)	39	24/287 (8.4%)	36
Neuropathy peripheral	1/300 (0.3%)	1	16/276 (5.8%)	18	8/287 (2.8%)	10
Peripheral sensory neuropathy	2/300 (0.7%)	2	16/276 (5.8%)	17	7/287 (2.4%)	9
Psychiatric disorders
Anxiety	15/300 (5%)	15	11/276 (4%)	12	15/287 (5.2%)	18
Insomnia	21/300 (7%)	23	28/276 (10.1%)	31	24/287 (8.4%)	30
Respiratory, thoracic and mediastinal disorders
Cough	40/300 (13.3%)	48	53/276 (19.2%)	65	37/287 (12.9%)	54
Dyspnoea	35/300 (11.7%)	43	19/276 (6.9%)	20	18/287 (6.3%)	27
Epistaxis	5/300 (1.7%)	6	9/276 (3.3%)	11	22/287 (7.7%)	34
Oropharyngeal pain	9/300 (3%)	9	14/276 (5.1%)	15	20/287 (7%)	23
Productive cough	17/300 (5.7%)	20	11/276 (4%)	11	6/287 (2.1%)	6
Skin and subcutaneous tissue disorders
Alopecia	1/300 (0.3%)	1	15/276 (5.4%)	15	15/287 (5.2%)	15
Dermatitis acneiform	8/300 (2.7%)	9	1/276 (0.4%)	1	83/287 (28.9%)	129
Dry skin	13/300 (4.3%)	16	10/276 (3.6%)	11	37/287 (12.9%)	48
Palmar-plantar erythrodysaesthesia syndrome	2/300 (0.7%)	2	4/276 (1.4%)	6	22/287 (7.7%)	31
Pruritus	32/300 (10.7%)	39	24/276 (8.7%)	26	30/287 (10.5%)	49
Rash	30/300 (10%)	42	29/276 (10.5%)	34	111/287 (38.7%)	159
Rash maculo-papular	9/300 (3%)	9	9/276 (3.3%)	10	16/287 (5.6%)	24
Skin fissures	0/300 (0%)	0	2/276 (0.7%)	3	38/287 (13.2%)	50
Vascular disorders
Hypertension	13/300 (4.3%)	14	17/276 (6.2%)	26	15/287 (5.2%)	18
Hypotension	6/300 (2%)	8	10/276 (3.6%)	11	20/287 (7%)	32

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this 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.