Clinical Trial Results:
A Phase 3 Clinical Trial of Pembrolizumab (MK-3475) in First Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
Summary
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EudraCT number |
2014-003698-41 |
Trial protocol |
SE EE LV DK FI AT CZ NL HU ES RO GR DE IT GB PL |
Global end of trial date |
19 Jul 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Jun 2024
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First version publication date |
23 Jun 2024
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MK-3475-048
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02358031 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Merck: KEYNOTE-048 | ||
Sponsors
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Sponsor organisation name |
Merck Sharp & Dohme LLC
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Sponsor organisation address |
126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
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Public contact |
Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
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Scientific contact |
Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 Jul 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Feb 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Jul 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
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) by Blinded Independent Central Review (BICR), prolongs overall survival (OS) compared to standard treatment, and 2) pembrolizumab combination therapy prolongs PFS per RECIST 1.1 by BICR and prolongs OS compared to standard treatment.
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Mar 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Argentina: 13
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Country: Number of subjects enrolled |
Australia: 51
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Country: Number of subjects enrolled |
Austria: 33
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Country: Number of subjects enrolled |
Brazil: 81
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Country: Number of subjects enrolled |
Canada: 39
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Country: Number of subjects enrolled |
Chile: 9
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Country: Number of subjects enrolled |
Colombia: 8
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Country: Number of subjects enrolled |
Czechia: 26
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Country: Number of subjects enrolled |
Denmark: 7
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Country: Number of subjects enrolled |
Estonia: 8
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Country: Number of subjects enrolled |
Finland: 5
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Greece: 19
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Country: Number of subjects enrolled |
Hong Kong: 1
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Country: Number of subjects enrolled |
Hungary: 28
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Country: Number of subjects enrolled |
Israel: 21
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Country: Number of subjects enrolled |
Italy: 28
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Country: Number of subjects enrolled |
Japan: 67
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Country: Number of subjects enrolled |
Latvia: 14
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Country: Number of subjects enrolled |
Malaysia: 12
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Country: Number of subjects enrolled |
Mexico: 27
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Country: Number of subjects enrolled |
Netherlands: 11
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Country: Number of subjects enrolled |
Norway: 16
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Country: Number of subjects enrolled |
Peru: 3
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Country: Number of subjects enrolled |
Philippines: 20
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Country: Number of subjects enrolled |
Poland: 3
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Country: Number of subjects enrolled |
Russian Federation: 14
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Country: Number of subjects enrolled |
Singapore: 1
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Country: Number of subjects enrolled |
South Africa: 13
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Country: Number of subjects enrolled |
Spain: 41
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Country: Number of subjects enrolled |
Sweden: 12
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Country: Number of subjects enrolled |
Switzerland: 16
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Country: Number of subjects enrolled |
Taiwan: 37
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Country: Number of subjects enrolled |
Thailand: 28
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Country: Number of subjects enrolled |
Türkiye: 26
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Country: Number of subjects enrolled |
United Kingdom: 10
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Country: Number of subjects enrolled |
United States: 131
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Worldwide total number of subjects |
882
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EEA total number of subjects |
254
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
565
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From 65 to 84 years |
315
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85 years and over |
2
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Recruitment
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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
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Screening details |
Of 1228 participants screened, 882 were randomized: pembro mono, pembro combo, or control arms. 22 participants in the control arm enrolled during an enrollment pause of pembro combo arm and were omitted from efficacy analyses between the respective arms. Per protocol, second course events were not included in efficacy or safety endpoints. | ||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pembrolizumab Monotherapy (Pembro Mono) | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year). | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pembrolizumab
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Investigational medicinal product code |
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Other name |
KEYTRUDA®, MK-3475
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years)
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Arm title
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Pembrolizumab + Chemotherapy (Pembro Combo) | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants received 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-Fluorouracil (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]). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year). | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pembrolizumab
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Investigational medicinal product code |
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Other name |
KEYTRUDA®, MK-3475
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years)
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Investigational medicinal product name |
5-Fluorouracil (5-FU)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months])
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Investigational medicinal product name |
Carboplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Carboplatin at a target Area Under the Curve of 5 (AUC 5) IV on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months])
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Investigational medicinal product name |
Cisplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
100 mg/m^2 IV Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months])
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Arm title
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Cetuximab + Chemotherapy (Control) | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
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 [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]). | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Cetuximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
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
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Investigational medicinal product name |
5-FU
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months])
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Investigational medicinal product name |
Carboplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
AUC 5 IV Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months])
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Investigational medicinal product name |
Cisplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
100 mg/m^2 IV Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months])
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Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Per protocol, efficacy analyses were performed by comparing the Pembro Combo arm versus the Control arm. Due to a pause in enrollment in the Pembro Combo arm, only the concurrent control arm is used for their comparison. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Per protocol, efficacy analyses were performed by comparing the Pembro Mono arm versus the Control arm. Due to a pause in enrollment in the Pembro Combo arm, only the concurrent control arm is used for their comparison. |
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Baseline characteristics reporting groups
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Reporting group title |
Pembrolizumab Monotherapy (Pembro Mono)
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Reporting group description |
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pembrolizumab + Chemotherapy (Pembro Combo)
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Reporting group description |
Participants received 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-Fluorouracil (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]). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cetuximab + Chemotherapy (Control)
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Reporting group description |
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 [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]). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pembrolizumab Monotherapy (Pembro Mono)
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Reporting group description |
Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year). | ||
Reporting group title |
Pembrolizumab + Chemotherapy (Pembro Combo)
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||
Reporting group description |
Participants received 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-Fluorouracil (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]). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year). | ||
Reporting group title |
Cetuximab + Chemotherapy (Control)
|
||
Reporting group description |
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 [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]). |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented progressive disease (PD) per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the sum of diameters (SOD) of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol PFS in the pembro combo versus the control arm was a pre-specified primary analysis of the Intent-To-Treat (ITT) population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. PFS is reported here for the first course, for all participants in the pembro combo and control arm. Per protocol PFS was compared separately between all participants of the pembro mono and control arm and is presented later.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [1] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
PFS in All Participants | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
559
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.21211 [2] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.93
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.78 | ||||||||||||||||
upper limit |
1.11 | ||||||||||||||||
Notes [2] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status. |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurrs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by immunohistochemistry (IHC) as Combined Positive Score ≥1 (CPS ≥1). 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. PFS is reported here for the first course of treatment, for all participants in the pembro combo and control arm with CPS ≥1. Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [3] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
PFS in participants with CPS≥1 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
477
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.03697 [4] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.84
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.69 | ||||||||||||||||
upper limit |
1.02 | ||||||||||||||||
Notes [4] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status. |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as Combined Positive Score ≥20 (CPS ≥20). 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. PFS is reported here for the first course, for all participants in the pembro combo and control arm with CPS ≥20. Per protocol, PFS was compared separately between CPS ≥20 participants of the pembro mono and control arm and is presented later.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [5] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
PFS in participants with CPS≥20 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
236
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.02951 [6] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.76
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.58 | ||||||||||||||||
upper limit |
1.01 | ||||||||||||||||
Notes [6] - One-sided p-value based on log-rank test stratified by ECOG and HPV status. |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: Overall Survival (OS) in All Participants | ||||||||||||||||
End point 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 versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. OS is reported here for the first course, for all participants in the pembro combo and control arm. Per protocol, OS was compared separately between all participants of the pembro mono arm and control arm and is presented later.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [7] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
OS in All Participants | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
559
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.00025 [8] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.72
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.6 | ||||||||||||||||
upper limit |
0.87 | ||||||||||||||||
Notes [8] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status. |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥1 | ||||||||||||||||
End point 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 versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS≥1. 20 participants in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. OS is reported here for the first course, 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.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [9] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
OS in participants with CPS≥1 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
477
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0 [10] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.65
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.53 | ||||||||||||||||
upper limit |
0.8 | ||||||||||||||||
Notes [10] - p-value = 0.00002; One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status. |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥20 | ||||||||||||||||
End point 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 versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS≥20. 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. OS is reported here for the first course, for all participants in the pembro combo and control arm with CPS≥20. Per protocol, OS was compared separately between CPS ≥20 participants of the pembro mono arm and control arm and is presented later.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [11] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
OS in participants with CPS≥20 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
236
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.00044 [12] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.6
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.45 | ||||||||||||||||
upper limit |
0.82 | ||||||||||||||||
Notes [12] - One-sided p-value based on log-rank test stratified by ECOG and HPV status. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: PFS per RECIST 1.1 by BICR in All Participants | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment. PFS is reported here for the first course, 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.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [13] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
PFS in All Participants | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
601
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.9983 [14] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
1.29
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
1.09 | ||||||||||||||||
upper limit |
1.53 | ||||||||||||||||
Notes [14] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. PFS is reported here for the first course, for all participants in the pembro mono and control arm with CPS≥1. Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [15] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
PFS in participants with CPS≥1 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
512
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.8958 [16] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
1.13
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.94 | ||||||||||||||||
upper limit |
1.36 | ||||||||||||||||
Notes [16] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. PFS is reported here for the first course, for all participants in the pembro mono and control arm with CPS ≥20. Per protocol, PFS was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [17] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
PFS in participants with CPS≥20 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
255
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.46791 [18] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.99
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.76 | ||||||||||||||||
upper limit |
1.29 | ||||||||||||||||
Notes [18] - One-sided p-value based on log-rank test stratified by ECOG and HPV status. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: OS in All Participants | ||||||||||||||||
End point 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 versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment. OS is reported here for the first course, for all participants in the pembro mono and control arm. Per protocol, OS was compared separately between all participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [19] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
OS in All Participants | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
601
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.01985 [20] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.83
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.7 | ||||||||||||||||
upper limit |
0.99 | ||||||||||||||||
Notes [20] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥1 | ||||||||||||||||
End point 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 versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. OS is reported here for the first course, for all participants in the pembro mono and control arm with CPS ≥1. Per protocol, OS was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [21] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
OS in participants with CPS≥1 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
512
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.00133 [22] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.74
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.61 | ||||||||||||||||
upper limit |
0.9 | ||||||||||||||||
Notes [22] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥20 | ||||||||||||||||
End point 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 versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. OS is reported here for the first course, for all participants in the pembro mono arm and control arm with CPS ≥20. Per protocol, OS was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [23] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
OS in participants with CPS≥20 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
255
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0001 [24] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.58
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.44 | ||||||||||||||||
upper limit |
0.78 | ||||||||||||||||
Notes [24] - One-sided p-value based on log-rank test stratified by ECOG and HPV status. |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among All Participants | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for 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.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 6
|
||||||||||||||||
|
|||||||||||||||||
Notes [25] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo versus control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. 20 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants in the pembro combo and control arm with CPS ≥1. Per protocol, PFS rate at 6 months was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 6
|
||||||||||||||||
|
|||||||||||||||||
Notes [26] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants in the pembro combo and control arm with CPS≥20. Per protocol, PFS rate at 6 months was compared separately between CPS ≥20 participants of the pembro mono and control arm and is presented later.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 6
|
||||||||||||||||
|
|||||||||||||||||
Notes [27] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among All Participants | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants in the pembro combo and control arm. Per protocol, the percentage of participants with PFS at 12 months was compared separately between all participants of the pembro mono and control arm and is presented later.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 12
|
||||||||||||||||
|
|||||||||||||||||
Notes [28] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. 20 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants with in the pembro combo arm and control arm with CPS≥1. Per protocol, PFS rate at 12 months was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 12
|
||||||||||||||||
|
|||||||||||||||||
Notes [29] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants in the pembro combo and control arm with CPS ≥20. Per protocol, PFS rate at 12 months was compared separately between CPS ≥20 participants of the pembro mono and control arm and is presented later.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 12
|
||||||||||||||||
|
|||||||||||||||||
Notes [30] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: Objective Response Rate (ORR) per RECIST 1.1 by BICR in All Participants | ||||||||||||||||
End point 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. by BICR. Per protocol, ORR in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, 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.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [31] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
ORR in all participants | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
559
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.574 [32] | ||||||||||||||||
Method |
Miettinen & Nurminen method | ||||||||||||||||
Parameter type |
Difference in ORR Percentage | ||||||||||||||||
Point estimate |
-0.8
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-8.7 | ||||||||||||||||
upper limit |
7.2 | ||||||||||||||||
Notes [32] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 | ||||||||||||||||
End point 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. by BICR. Per protocol, ORR in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. 20 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro combo arm and control arm with CPS ≥1. Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [33] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
ORR in participants with CPS≥1 | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
477
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.4586 [34] | ||||||||||||||||
Method |
Miettinen & Nurminen method | ||||||||||||||||
Parameter type |
Difference in ORR Percentage | ||||||||||||||||
Point estimate |
0.5
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-8.2 | ||||||||||||||||
upper limit |
9.1 | ||||||||||||||||
Notes [34] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
EORTC-QLQ-C30 is a 30-item questionnaire to assess the quality of life (QoL) of cancer patients. Responses to "How would you rate your overall health during the past week?" (Item 29) and "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 so scores ranged from 0 to 100; a higher score indicating a better overall outcome. Per protocol change from baseline (BL) to Week 15 in GHS/QoL combined score, for the first course, in all participants of the pembro combo versus control arm was a pre-specified secondary analysis; and compared separately between all participants of pembro mono and control arm, as presented later. All participants in the pembro combo and control arm who got ≥1 dose of study drug and had assessments available at- or post-BL up to Week 15 were analyzed. 20 in the control arm in an enrollment pause of pembro combo arm were excluded.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||||||
|
|||||||||||||||||
Notes [35] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
Change from Baseline: EORTC QLQ-C30 Items 29 & 30 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
527
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.839 [36] | ||||||||||||||||
Method |
constrained Longitudinal Data Analysis | ||||||||||||||||
Parameter type |
Difference in LS Means | ||||||||||||||||
Point estimate |
0.4
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.46 | ||||||||||||||||
upper limit |
4.26 | ||||||||||||||||
Notes [36] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20 | ||||||||||||||||
End point 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. by BICR. Per protocol, ORR in the pembro combo arm versus the control arm as a pre-specified secondary analysis of the ITT population, consisting of consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro combo arm and control arm with CPS≥20. Per protocol, ORR was compared separately between CPS ≥20 participants of the pembro mono arm and control arm and is presented later.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [37] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
ORR in participants with CPS≥20 | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
236
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.2161 [38] | ||||||||||||||||
Method |
Miettinen & Nurminen method | ||||||||||||||||
Parameter type |
Difference in ORR Percentage | ||||||||||||||||
Point estimate |
5
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-7.5 | ||||||||||||||||
upper limit |
17.4 | ||||||||||||||||
Notes [38] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point 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) | ||||||||||||||||
End point description |
EORTC-QLQ-C30 is a 30-item questionnaire assessing QoL of cancer patients. Response to "How would you rate your overall health during the past week?" (Item 29) and "How would you rate your overall QoL during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating a better outcome. TTD is the time from BL to first onset of a ≥10-point decrease from BL in GHS/QoL score. Per protocol TTD for the first course, in all participants of pembro combo versus control arm was a pre-specified secondary analysis; TTD in pembro mono versus control arm was presented later. All participants in the pembro combo and control arms who completed EORTC QLQ-C30 and got ≥1 dose of study drug were analyzed. 20 in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. 9999: Value not reached due to insufficient number of participants with event.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline up to approximately 12 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [39] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
TTD: EORTC QLQ-C30 Items 29 & 30 | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
530
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.9497 [40] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
1.37
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.94 | ||||||||||||||||
upper limit |
2 | ||||||||||||||||
Notes [40] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: TTD in the EORTC QLQ- Head and Neck Module 35 (H&N35) Pain Score (Kaplan-Meier Method) | ||||||||||||||||
End point description |
ORTC QLQ-H&N35 is a 35-item questionnaire to assess QoL of head and neck cancer patients (7 multi-item scales to assess pain, swallowing, senses, speech, social eating, social contact, sexuality). 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 so scores ranged from 0 to 100; a higher score indicating more problems. TTD is the time from BL to first onset of a ≥10-point decrease from BL. Per protocol TTD in Pain Score for first course, in all participants of pembro combo versus control arm was a pre-specified secondary analysis; TTD in pembro mono versus control arm was presented later. All participants in the pembro combo and control arm who got ≥1 dose of study drug and completed EORTC QLQ-H&N35 were analyzed, 20 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. 9999: Value not reached due to insufficient number of participants with event.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline up to approximately 12 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [41] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
TTD: EORTC QLQ-H&N35 Pain Score | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
528
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.9476 [42] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
1.37
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.93 | ||||||||||||||||
upper limit |
2.02 | ||||||||||||||||
Notes [42] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Combo vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score (Kaplan-Meier Method) | ||||||||||||||||
End point description |
EORTC QLQ-H&N35 is a 35-item questionnaire to assess QoL of head and neck cancer patients (7 multi-item scales to assess pain, swallowing, senses, speech, social eating, social contact, sexuality). Responses to Swallowing scale (Items 35-38) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating more problems. TTD is the time from BL to the first onset of a ≥10-point decrease from BL. Per protocol TTD for the first course, in all participants of the pembro combo versus control arm was a pre-specified secondary analysis; TTD in pembro mono versus control arm was presented later. All participants in the pembro combo and control arm who completed the EORTC QLQ-H&N35 and got ≥1 dose of study drug were analyzed; 20 enrolled in control arm during an enrollment pause of the pembro combo arm were excluded. 9999: Value not reached due to insufficient number of participants with event.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline up to approximately 12 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [43] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
TTD: EORTC QLQ-H&N35 Swallowing Score | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
528
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.5836 [44] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
1.05
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.69 | ||||||||||||||||
upper limit |
1.59 | ||||||||||||||||
Notes [44] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among All Participants | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants in the pembro mono arm and control arm. Per protocol, PFS rate at 6 months was compared separately between all participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 6
|
||||||||||||||||
|
|||||||||||||||||
Notes [45] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants in the pembro mono arm and control arm with CPS≥1. 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.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 6
|
||||||||||||||||
|
|||||||||||||||||
Notes [46] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among All Participants | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for 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.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 12
|
||||||||||||||||
|
|||||||||||||||||
Notes [47] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants with in the pembro mono arm and control arm with CPS≥20. Per protocol, PFS rate at 6 months was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 6
|
||||||||||||||||
|
|||||||||||||||||
Notes [48] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants in the pembro mono and control arm with CPS≥1. Per protocol, the percentage of participants with PFS at 12 months was compared separately between CPS ≥1 participants of the pembro combo and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 12
|
||||||||||||||||
|
|||||||||||||||||
Notes [49] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
PFS is the time from randomization the first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm as a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS≥20. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants in the pembro mono and control arm with CPS≥20. Per protocol, the percentage of participants with PFS at 12 months was compared separately between CPS ≥20 participants of the pembro combo and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Month 12
|
||||||||||||||||
|
|||||||||||||||||
Notes [50] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: ORR per RECIST 1.1 by BICR in All Participants | ||||||||||||||||
End point 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. by BICR. Per protocol, ORR in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro mono and control arm. Per protocol, ORR was compared separately between all participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [51] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
Pembro Mono vs Control: ORR in all subjects | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
601
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 1 [52] | ||||||||||||||||
Method |
Miettinen & Nurminen method | ||||||||||||||||
Parameter type |
Difference in ORR Percentage | ||||||||||||||||
Point estimate |
-19
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-25.8 | ||||||||||||||||
upper limit |
-12.1 | ||||||||||||||||
Notes [52] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 | ||||||||||||||||
End point 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. by BICR. Per protocol, ORR in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro mono and control arm with CPS≥1. Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [53] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
Pembro Mono vs Control: ORR subjects with CPS ≥1 | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
512
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 1 [54] | ||||||||||||||||
Method |
Miettinen & Nurminen method | ||||||||||||||||
Parameter type |
Difference in ORR Percentage | ||||||||||||||||
Point estimate |
-15.9
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-23.4 | ||||||||||||||||
upper limit |
-8.3 | ||||||||||||||||
Notes [54] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20 | ||||||||||||||||
End point 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. by BICR. Per protocol, ORR in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro mono and control arm with CPS≥20. Per protocol, ORR was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [55] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
ORR in participants with CPS≥20 | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
255
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.9869 [56] | ||||||||||||||||
Method |
Miettinen & Nurminen method | ||||||||||||||||
Parameter type |
Difference in ORR Percentage | ||||||||||||||||
Point estimate |
-12.8
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-23.8 | ||||||||||||||||
upper limit |
-1.5 | ||||||||||||||||
Notes [56] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point 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 | ||||||||||||||||
End point description |
EORTC-QLQ-C30 is a 30-item questionnaire to assess the quality of life (QoL) of cancer patients. Responses to "How would you rate your overall health during the past week?" (Item 29) and "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. Per protocol, change from baseline to Week 15 in GHS/QoL combined score, for the first course, in all participants of the pembro mono versus control arm was a pre-specified secondary analysis; and compared separately between all participants of pembro combo and control arm and is presented earlier. All participants in the pembro mono arm and the control arm who got ≥1 dose of study drug and had assessments available at baseline or post-baseline up to Week 15 were analyzed.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||||||
|
|||||||||||||||||
Notes [57] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
Change from Baseline: EORTC QLQ-C30 Items 29 & 30 | ||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
573
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.893 [58] | ||||||||||||||||
Method |
constrained Longitudinal Data Analysis | ||||||||||||||||
Parameter type |
Difference in LS Means | ||||||||||||||||
Point estimate |
0.24
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.34 | ||||||||||||||||
upper limit |
3.82 | ||||||||||||||||
Notes [58] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: TTD in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score | ||||||||||||||||
End point description |
EORTC-QLQ-C30 is a 30-item questionnaire assessing QoL of cancer patients. Response to "How would you rate your overall health during the past week?" (Item 29) and "How would you rate your overall QoL during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating a better outcome. TTD is the time from BL to first onset of a ≥10-point decrease from BL in GHS/QoL score. Per protocol TTD for the first course, in all participants of pembro mono versus control arm was a pre-specified secondary analysis; TTD in pembro combo versus control arm was presented earlier. All participants in the pembro mono and control arms who completed EORTC QLQ-C30 and got ≥1 dose of study drug were analyzed. 9999: Value not reached due to insufficient number of participants with event.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline up to approximately 12 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [59] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
TTD: EORTC QLQ-C30 Items 29 & 30 | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
574
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.953 [60] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
1.38
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.95 | ||||||||||||||||
upper limit |
2 | ||||||||||||||||
Notes [60] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Pain Score | ||||||||||||||||
End point description |
EORTC QLQ-H&N35 is a 35-item questionnaire to assess QoL of head and neck cancer patients (7 multi-item scales to assess pain, swallowing, senses, speech, social eating, social contact, sexuality). 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 so scores ranged from 0 to 100; a higher score indicating more problems. TTD is the time from BL to first onset of a ≥10-point decrease from BL. Per protocol TTD in Pain Score for first course, in all participants of pembro mono versus control arm was a pre-specified secondary analysis; TTD in pembro combo versus control arm was presented earlier. All participants in the pembro mono and control arm who got ≥1 dose of study drug and completed EORTC QLQ-H&N35 were analyzed. 9999: Value not reached due to insufficient number of participants with event.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline up to approximately 12 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [61] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
TTD: EORTC QLQ-C30 H&N35 Pain Score | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
575
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.1501 [62] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.8
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.53 | ||||||||||||||||
upper limit |
1.21 | ||||||||||||||||
Notes [62] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||||||
End point title |
Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score | ||||||||||||||||
End point description |
EORTC QLQ-H&N35 is a 35-item questionnaire to assess QoL of head and neck cancer patients (7 multi-item scales to assess pain, swallowing, senses, speech, social eating, social contact, sexuality). Responses to Swallowing scale (Items 35-38) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating more problems. TTD is the time from BL to the first onset of a ≥10-point decrease from BL. Per protocol TTD for the first course, in all participants of the pembro mono versus control arm was a pre-specified secondary analysis; TTD in pembro combo versus control arm was presented earlier. All participants in the pembro mono and control arm who completed the EORTC QLQ-H&N35 and got ≥1 dose of study drug were analyzed. 9999: Value not reached due to insufficient number of participants with event.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline up to approximately 12 months
|
||||||||||||||||
|
|||||||||||||||||
Notes [63] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint. |
|||||||||||||||||
Statistical analysis title |
TTD: EORTC QLQ-H&N35 Swallowing Score | ||||||||||||||||
Statistical analysis description |
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).
|
||||||||||||||||
Comparison groups |
Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
|
||||||||||||||||
Number of subjects included in analysis |
575
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
P-value |
= 0.8751 [64] | ||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
1.26
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.85 | ||||||||||||||||
upper limit |
1.88 | ||||||||||||||||
Notes [64] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison. |
|
|||||||||||||
End point title |
Number of Participants Experiencing an Adverse Event (AE) | ||||||||||||
End point 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, for the first course of treatment, in subjects who received ≥1 dose of study drug, was reported for each arm.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Number of Participants Who Discontinued Study Drug Due to an AE | ||||||||||||
End point 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, for the first course of treatment, in subjects who received ≥1 dose of study drug, was reported for each arm.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 47 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to approximately 98 months
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All Cause Mortality (ACM): all randomized participants. AEs: all randomized participants who got ≥1 dose of study drug. Per protocol, MedDRA preferred terms “Neoplasm progression (NP), Malignant (NP) and Disease progression” not related to study drug are omitted as AEs; ACM and AEs collected and reported separately for pembrolizumab second course.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pembrolizumab Monotherapy (Pembro Mono)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pembrolizumab + Chemotherapy (Pembro Combo)
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Reporting group description |
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Reporting group title |
Pembrolizumab + Chemotherapy Second Course
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pembrolizumab Monotherapy Second Course
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cetuximab + Chemotherapy (Control)
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Reporting group description |
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Jul 2015 |
Amendment 1 included an increase in sample size. The sample size increased from 750 to 780 based on prevalence of strongly positive PD-L1 expression seen in data from the HNSCC cohorts in other MK-3475 Pembrolizumab studies. Added PFS hypothesis for pembrolizumab in combination with chemotherapy vs. standard treatment in subjects with strongly positive PD-L1 expression. |
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06 Sep 2015 |
Amendment 5 included changes to OS. OS was changed from a secondary objective to a primary objective, and biomarker population was updated to include PD-L1 ≥20% CPS, ≥10% CPS, ≥1% CPS. Sample size increased from 780 to 825 due to these changes. The strongly positive PD-L1 enrichment population was removed. Added QOL secondary objectives. Changed ORR, DOR, and PFS per irRECIST from secondary to exploratory objectives. Modified inclusion and exclusion criteria. |
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06 Apr 2017 |
Amendment 7 included references to PD-L1 10% Combined Positive Score were removed; only the 20% and 1% cut points are planned to be analyzed. |
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13 Sep 2017 |
Amendment 8 included follow-up time was increased at the interim and final analyses by 3 months to achieve data maturity at these timepoints. |
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27 Nov 2017 |
Amendment 9 included dose modification guidelines were updated per health authority feedback. Hypotheses for PFS and OS superiority in biomarker positive subpopulation were added. Follow-up time was increased at the second interim analysis and final analysis to allow adequate follow-up time to assess long-term effects of pembrolizumab. Language was added to enable survival follow-up activities throughout the study at timepoints specified by the Sponsor. |
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30 Jan 2019 |
Amendment 10 modified to indicate the number of expected events, rather than required events, references to “event-driven” were removed, and text was modified to describe the timing of the final analysis to account for the scenario if the number of deaths for one hypothesis accumulates slower than expected to prevent the trial continuing for an unreasonable period for the final analysis. |
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21 Apr 2020 |
Amendment 11 corrected the typographical error "co-primary" that appears at the end of the second paragraph in Section 4.2.3.1.1 has been corrected to "dual-primary" to indicate that the 2 primary endpoints in the study, OS and PFS, were "dual-primary" endpoints rather than "co-primary" endpoints. As a result, the study is considered positive if a statistically significant result is determined for either of these endpoints. This error has appeared in all versions of the protocol starting with amendment 048-05, dated 05-AUG-2016. |
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10 Jun 2021 |
Amendment 12 updated the pembrolizumab dose modification table and toxicity management guidelines for irAEs, in line with FDA request to harmonize the presentation of safety information across all FDA-approved PD-1/L-1 antibody prescribing information. To align with the updated SmPC for cetuximab. |
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21 Jul 2022 |
Amendment 13 added language to allow subjects to roll over to a pembrolizumab extension study. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |