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)

A Phase 3 Clinical Trial of Pembrolizumab (MK-3475) in First Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Head and Neck Cancer; Metastatic Head and Neck Cancer
• Intervention / Treatment: Biological: Cetuximab; Biological: Pembrolizumab; Drug: Cisplatin; Drug: Carboplatin; Drug: 5-FU

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).

Per protocol, response/progression or adverse events (AEs) that occur during the second pembrolizumab course will not be counted towards efficacy outcome measures or safety outcome measures, respectively.

• Study Type: Interventional
• Enrollment (Actual): 882
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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 35 cycles (up to ~2 years).	Biological: Pembrolizumab; Pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years).; Other Names: MK-3475; KEYTRUDA®
Experimental: Pembrolizumab + Chemotherapy (Pembro Combo); Participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years); 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 [up to ~4 months]); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months]).	Biological: Pembrolizumab; Pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years).; Other Names: MK-3475; KEYTRUDA®; Drug: Cisplatin; Cisplatin 100 mg/m^2 IV on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months]).; Drug: Carboplatin; Carboplatin at a target AUC 5 IV on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months]).; Drug: 5-FU; 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months]).
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 [up to ~4 months] 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 [up to ~4 months]).	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; Drug: Cisplatin; Cisplatin 100 mg/m^2 IV on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months]).; Drug: Carboplatin; Carboplatin at a target AUC 5 IV on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months]).; Drug: 5-FU; 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months]).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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 the first course of treatment, 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.	Up to approximately 47 months
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	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Combo vs Control: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Combo vs Control: Overall Survival (OS) in All Participants	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥1	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥20	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Mono vs Control: PFS Per RECIST 1.1 by BICR in All Participants	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Mono vs Control: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Mono vs Control: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Mono vs Control: OS in All Participants	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥1	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥20	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 the first course of treatment, 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.	Up to approximately 47 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pembro Combo vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among All Participants	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, for the first course of treatment, 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.	Month 6
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	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, for the first course of treatment, 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.	Month 6
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	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, for the first course of treatment, 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.	Month 6
Pembro Combo vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among All Participants	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, for the first course of treatment, 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.	Month 12
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	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, for the first course of treatment, 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.	Month 12
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	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, for the first course of treatment, 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.	Month 12
Pembro Combo vs Control: Objective Response Rate (ORR) Per RECIST 1.1 by BICR in All Participants	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Combo vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Combo vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20	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 the first course of treatment, 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.	Up to approximately 47 months
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	The EORTC-QLQ-C30 is a 30-item questionnaire 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; a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 15 in the GHS/QoL combined score, for the first course of treatment, was compared between all participants of the pembro combo arm and the control arm as a pre-specified secondary analysis. Per 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.	Baseline, Week 15
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)	EORTC-QLQ-C30 is a 30-item questionnaire 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; 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, for first course of treatment, was compared between all participants of pembro combo arm and control arm as a pre-specified secondary analysis; and 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.	Baseline up to approximately 12 months
Pembro Combo vs Control: TTD in the EORTC QLQ- Head and Neck Module 35 (H&N35) Pain Score (Kaplan-Meier Method)	EORTC QLQ-H&N35 is a 35-item questionnaire 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, for the first course of treatment, 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.	Baseline up to approximately 12 months
Pembro Combo vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score (Kaplan-Meier Method)	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; 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, for the first course of treatment, was compared between all participants of pembro combo arm and control arm as a pre-specified secondary analysis; and compared separately between all participants of pembro mono arm and control arm and is presented later in the record.	Baseline up to approximately 12 months
Pembro Mono vs Control: Percentage of Participants With PFS at 6 Months Per RECIST 1.1 by BICR Among All Participants	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, for the first course of treatment, 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.	Month 6
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	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, for the first course of treatment, 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.	Month 6
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	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, for the first course of treatment, 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.	Month 6
Pembro Mono vs Control: Percentage of Participants With PFS at 12 Months Per RECIST 1.1 by BICR Among All Participants	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, for the first course of treatment, 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.	Month 12
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	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, for the first course of treatment, 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.	Month 12
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	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, for the first course of treatment, 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.	Month 12
Pembro Mono vs Control: ORR Per RECIST 1.1 by BICR in All Participants	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Mono vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1	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 the first course of treatment, 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.	Up to approximately 47 months
Pembro Mono vs Control: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20	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 the first course of treatment, 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.	Up to approximately 47 months
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	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, for the first course of treatment, 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.	Baseline, Week 15
Pembro Mono vs Control: TTD in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score	EORTC-QLQ-C30 is a 30-item questionnaire 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; 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, for the first course of treatment, was compared between all participants of pembro mono arm and control arm as a pre-specified secondary analysis; and compared separately between all participants of pembro combo arm and control arm and is presented earlier in the record.	Baseline up to approximately 12 months
Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Pain Score	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; 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, for the first course of treatment, 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.	Baseline up to approximately 12 months
Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score	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; 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, for the first course of treatment, was compared between all participants of pembro mono arm and control arm as a pre-specified secondary analysis; and compared separately between all participants of pembro combo arm and control arm and is presented earlier in the record.	Baseline up to approximately 12 months
Number of Participants Experiencing an Adverse Event (AE)	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, for the first course of treatment, was reported for each arm.	Up to approximately 47 months
Number of Participants Who Discontinued Study Drug Due to an AE	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, for the first course of treatment, was reported for each arm.	Up to approximately 47 months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Takahashi S, Oridate N, Tanaka K, Shimizu Y, Fujimoto Y, Matsumoto K, Yokota T, Yamazaki T, Takahashi M, Ueda T, Hanai N, Yamaguchi H, Hara H, Yoshizaki T, Yasumatsu R, Nakayama M, Shiga K, Fujii T, Mitsugi K, Takahashi K, Nohata N, Gumuscu B, Swaby RF, Tahara M. First-line pembrolizumab +/- chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048. Int J Clin Oncol. 2022 Dec;27(12):1805-1817. doi: 10.1007/s10147-022-02233-6. Epub 2022 Oct 20.
• Rischin D, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Ishak WZW, Hong RL, Mendoza RG, Jia L, Chirovsky D, Norquist J, Jin F, Burtness B. Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048. Oral Oncol. 2022 May;128:105815. doi: 10.1016/j.oraloncology.2022.105815. Epub 2022 Apr 2.
• Burtness B, Rischin D, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Ge J, Swaby RF, Gumuscu B, Harrington K. Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. J Clin Oncol. 2022 Jul 20;40(21):2321-2332. doi: 10.1200/JCO.21.02198. Epub 2022 Mar 25.
• Harrington KJ, Burtness B, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Lin J, Gumuscu B, Swaby RF, Rischin D. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol. 2023 Feb 1;41(4):790-802. doi: 10.1200/JCO.21.02508. Epub 2022 Oct 11.
• Tahara M, Greil R, Rischin D, Harrington KJ, Burtness B, de Castro G, Psyrri A, Brana I, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Ishak WZW, Lin J, Gumuscu B, Lerman N, Soulieres D. Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up from the randomized phase III KEYNOTE-048 study. Eur J Cancer. 2025 May 15;221:115395. doi: 10.1016/j.ejca.2025.115395. Epub 2025 Apr 4.
• Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, Gonzalez Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. doi: 10.1016/S0140-6736(19)32591-7. Epub 2019 Nov 1.

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): March 19, 2015
• Primary Completion (Actual): February 25, 2019
• Study Completion (Actual): July 19, 2023

Study Registration Dates

• First Submitted: February 3, 2015
• First Submitted That Met QC Criteria: February 3, 2015
• First Posted (Estimated): February 6, 2015

Study Record Updates

• Last Update Posted (Actual): July 18, 2025
• Last Update Submitted That Met QC Criteria: July 8, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: 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: Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Recurrence; Head and Neck Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Cetuximab; Carboplatin; Pembrolizumab
• Other Study ID Numbers: 3475-048; MK-3475-048 (Other Identifier: MSD); KEYNOTE-048 (Other Identifier: MSD); 2014-003698-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No