Clinical Trial Results:
A Phase II Clinical Trial of Single Agent Pembrolizumab (MK-3475) in Subjects with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) Who Have Failed Platinum and Cetuximab
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Summary
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EudraCT number |
2014-002447-18 |
Trial protocol |
NO DK |
Global end of trial date |
18 Jun 2021
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Results information
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Results version number |
v1 |
This version publication date |
11 Jun 2022
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First version publication date |
11 Jun 2022
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Other versions |
v2 |
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 |
3475-055
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02255097 | ||
WHO universal trial number (UTN) |
- | ||
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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 |
18 Jun 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Apr 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Jun 2021
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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 |
This is a study of single-agent pembrolizumab (MK-3475) in participants with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) who have progressed on platinum-based and cetuximab therapy. The primary study hypothesis is that pembrolizumab will provide a clinically meaningful objective response rate (ORR).
With protocol amendment 05 (02-Jan-2018), once study participants have achieved the study objective or the study has ended, participants will be discontinued from this study and enrolled in an extension study to continue protocol-defined assessments and 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 |
24 Oct 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Denmark: 3
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Country: Number of subjects enrolled |
Norway: 3
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Country: Number of subjects enrolled |
United States: 166
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Worldwide total number of subjects |
172
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EEA total number of subjects |
6
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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) |
108
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From 65 to 84 years |
63
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85 years and over |
1
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Recruitment
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Recruitment details |
Participants were eligible to receive second course treatment with pembrolizumab if they met criteria for re-treatment. There were 3 participants who received second course treatment. Per protocol, data collected during the second course were not counted towards efficacy or safety outcome measures. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
Final analyses for all primary outcome measures were done at the protocol-specified primary outcome measure met date. The analyses for all secondary outcome measures and the collection of adverse events were done at the end of study date. One participant allocated to receive pembrolizumab was not treatment and was not eligible for analysis. | ||||||||||||||||||||
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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 |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||
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Arms
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Arm title
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Pembrolizumab | ||||||||||||||||||||
Arm description |
Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Pembrolizumab
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Investigational medicinal product code |
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Other name |
KEYTRUDA®
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
200 mg administered by IV infusion on Day 1 of each 3-week cycle for up to 24 months
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pembrolizumab
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Reporting group description |
Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for retreatment. | ||
Subject analysis set title |
Pembrolizumab
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment.
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Subject analysis set title |
Pembrolizumab First Course
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment.
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Subject analysis set title |
Pembrolizumab Second Course
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Participants who met the criteria for retreatment received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 1 year of treatment.
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Subject analysis set title |
Strong PD-L1 TPS Positive Participants
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with strong programmed cell death ligand 1 (PD-L1) positive expression status, defined as a PD-L1 tumor proportion score (TPS) ≥50%, received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment.
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Subject analysis set title |
PD-L1 TPS Positive Participants
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with programmed cell death ligand 1 (PD-L1) positive expression status, defined as a PD-L1 tumor proportion score (TPS) ≥1%, received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment.
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Subject analysis set title |
PD-L1 CPS Positive Participants
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with programmed cell death ligand 1 (PD-L1) positive expression status, defined as a PD-L1 combined positive score (CPS) ≥1%, received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment.
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Subject analysis set title |
Participants With a HPV-positive Tumor Biopsy
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with a human papillomavirus (HPV) tumor biopsy received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment.
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Subject analysis set title |
Duplicate Pembrolizumab Arm
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment. This duplicate arm is added as a workaround to accommodate the statistical analysis of the single arm to a fixed efficacy target within the electronic application.
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Subject analysis set title |
Duplicate Strong PD-L1 TPS Positive Participants
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with strong programmed cell death ligand 1 (PD-L1) positive expression status, defined as a PD-L1 tumor proportion score (TPS) ≥50%, received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment. This duplicate arm is added as a workaround to accommodate the statistical analysis of the single arm to a fixed efficacy target within the electronic application.
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Subject analysis set title |
Duplicate PD-L1 TPS Positive Participants
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with programmed cell death ligand 1 (PD-L1) positive expression status, defined as a PD-L1 tumor proportion score (TPS) ≥1%, received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment. This duplicate arm is added as a workaround to accommodate the statistical analysis of the single arm to a fixed efficacy target within the electronic application.
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Subject analysis set title |
Duplicate Participants With a HPV-positive Tumor Biopsy
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants with a human papillomavirus (HPV) tumor biopsy received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment. This duplicate arm is added as a workaround to accommodate the statistical analysis of the single arm to a fixed efficacy target within the electronic application.
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End point title |
Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants | ||||||||||||
End point description |
ORR was assessed by RECIST 1.1 by performing imaging every 6-9 weeks after the first dose of treatment. ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR) defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to <10 mm or Partial Response (PR) defined as at least a 30% decrease in the sum of diameters (SPD) of target lesions, using the baseline SPD as a reference. Participants with missing data were considered non-responders. The analysis included all participants who received ≥1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
Up to 36 months
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Statistical analysis title |
ORR Comparison to Fixed Efficacy Target | ||||||||||||
Statistical analysis description |
ORR was evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 5% using an exact test of binomial distribution.
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Comparison groups |
Pembrolizumab v Duplicate Pembrolizumab Arm
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Number of subjects included in analysis |
342
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [1] | ||||||||||||
Method |
exact binomial distribution | ||||||||||||
Confidence interval |
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| Notes [1] - null hypothesis (H0): p ≤0.05 versus alternate hypothesis (H1): p >0.05 |
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End point title |
Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Strong Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||||||
End point description |
Participants with a strong PD-L1 expression status were evaluated for ORR by RECIST 1.1. The expression of PD-L1 was determined by immunohistochemistry (IHC) and strong PD-L1 positive was defined as a PD-L1 tumor proportion score (TPS) ≥50%. ORR was assessed by performing imaging every 6-9 weeks after the first dose of treatment. ORR was defined as the percentage of participants in the analysis population who had a CR defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to <10 mm or PR defined as at least a 30% decrease in the SPD of target lesions, using the baseline SPD as a reference. Participants with missing data were considered non-responders. The analysis included all participants who received ≥1 dose of study treatment with a TPS ≥50%.
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End point type |
Primary
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End point timeframe |
Up to 36 months
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Statistical analysis title |
ORR Comparison to Fixed Efficacy Target | ||||||||||||
Statistical analysis description |
ORR was evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 5% using an exact test of binomial distribution.
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Comparison groups |
Strong PD-L1 TPS Positive Participants v Duplicate Strong PD-L1 TPS Positive Participants
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [2] | ||||||||||||
Method |
exact binomial distribution | ||||||||||||
Confidence interval |
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| Notes [2] - null hypothesis (H0): p ≤0.05 versus alternate hypothesis (H1): p >0.05 |
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End point title |
Number of Participants Experiencing an Adverse Event (AE) [3] | ||||||
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 treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the product, whether or not considered related to the product. Worsening of a preexisting condition temporally associated with the use of the product was also an AE. A serious adverse event was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, or was another important medical event. Per protocol, analysis for this outcome measure was performed during the initial (first) course of therapy. The analysis included all participants who received ≥1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
Up to 27 months
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: There was no statistical analysis planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants Discontinuing Study Drug Due to an AE [4] | ||||||
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 treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the product, whether or not considered related to the product. Worsening of a preexisting condition temporally associated with the use of the product was also an AE. A serious adverse event was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, or was another important medical event. Per protocol, analysis for this outcome measure was performed during the initial (first) course of therapy. The analysis included all participants who received ≥1 dose of study treatment.
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End point type |
Primary
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End point timeframe |
Up to 24 months
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: There was no statistical analysis planned for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||||||
End point description |
Participants with a positive PD-L1 expression status were evaluated for ORR by RECIST 1.1. PD-L1 expression was determined by IHC and PD-L1 positive was defined as a PD-L1 TPS ≥1%. ORR was assessed by performing imaging every 6-9 weeks after the first dose of treatment. ORR was defined as the percentage of participants in the analysis population who had a CR defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to <10 mm or PR defined as at least a 30% decrease in the SPD of target lesions, using the baseline SPD as a reference. Participants with missing data were considered non-responders. The analysis included all participants who received ≥1 dose of study treatment with a TPS ≥1%.
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End point type |
Secondary
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End point timeframe |
Up to 76.9 months
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Statistical analysis title |
ORR Comparison to Fixed Efficacy Target | ||||||||||||
Statistical analysis description |
ORR was evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 5% using an exact test of binomial distribution.
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Comparison groups |
PD-L1 TPS Positive Participants v Duplicate PD-L1 TPS Positive Participants
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Number of subjects included in analysis |
242
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [5] | ||||||||||||
Method |
exact binomial distribution | ||||||||||||
Confidence interval |
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| Notes [5] - null hypothesis (H0): p ≤0.05 versus alternate hypothesis (H1): p >0.05 |
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End point title |
Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Human Papillomavirus (HPV) Positive Tumors | ||||||||||||
End point description |
Participants with a HPV-positive tumor biopsy were evaluated for ORR by RECIST 1.1. ORR was assessed by performing imaging every 6-9 weeks after the first dose of treatment. ORR was defined as the percentage of participants in the analysis population who had a CR defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to <10 mm or PR defined as at least a 30% decrease in the SPD of target lesions, using the baseline SPD as a reference. Participants with missing data were considered non-responders. The analysis included all participants who received ≥1 dose of study treatment with a HPV-positive tumor.
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End point type |
Secondary
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End point timeframe |
Up to 76.9 months
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Statistical analysis title |
ORR Comparison to Fixed Efficacy Target | ||||||||||||
Statistical analysis description |
ORR was evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 5% using an exact test of binomial distribution.
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Comparison groups |
Participants With a HPV-positive Tumor Biopsy v Duplicate Participants With a HPV-positive Tumor Biopsy
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Number of subjects included in analysis |
142
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0027 [6] | ||||||||||||
Method |
exact binomial distribution | ||||||||||||
Confidence interval |
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| Notes [6] - null hypothesis (H0): p ≤0.05 versus alternate hypothesis (H1): p >0.05 |
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End point title |
Objective Response Rate (ORR) by Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants | ||||||||||||
End point description |
ORR was assessed by modified RECIST 1.1 by performing imaging every 6-9 weeks after the first dose. ORR was defined as the percentage of participants who had a CR defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to <10 mm or PR defined as at least a 30% decrease in the sum of diameters of target lesions, using the baseline SPD as a reference. If imaging shows disease progression (PD) imaging was repeated 4 weeks later for confirmation. PD was defined as ≥20% increase in SPD of target lesions and new measurable lesions, taking as reference the smallest sum recorded since treatment started. Participants with missing data were considered non-responders. The analysis included all participants who received ≥1 dose of study treatment.
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End point type |
Secondary
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End point timeframe |
Up to 76.9 months
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Statistical analysis title |
ORR Comparison to Fixed Efficacy Target | ||||||||||||
Statistical analysis description |
ORR was evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 5% using an exact test of binomial distribution.
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Comparison groups |
Pembrolizumab v Duplicate Pembrolizumab Arm
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Number of subjects included in analysis |
342
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [7] | ||||||||||||
Method |
exact binomial distribution | ||||||||||||
Confidence interval |
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| Notes [7] - null hypothesis (H0): p ≤0.05 versus alternate hypothesis (H1): p >0.05 |
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End point title |
Objective Response Rate (ORR) by Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||||||
End point description |
Participants with a positive PD-L1 expression status were evaluated for ORR by modified RECIST 1.1. PD-L1 expression was determined by IHC and PD-L1 positive was defined as a TPS ≥1%. ORR was assessed by imaging every 6-9 weeks after the first dose. ORR was defined as the percentage of participants who had a CR defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to <10 mm or PR defined as at least a 30% decrease in the SPD of target lesions, using the baseline SPD as a reference. If imaging shows PD imaging was repeated 4 weeks later for confirmation. PD was defined as ≥20% increase in the SPD of target lesions and new measurable lesions, taking as reference the smallest sum recorded since treatment started. Participants with missing data were considered non-responders. The analysis included all participants who received ≥1 dose of study treatment with a tumor proportion score ≥1%.
|
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End point type |
Secondary
|
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End point timeframe |
Up to 76.9 months
|
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|
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Statistical analysis title |
ORR Comparison to Fixed Efficacy Target | ||||||||||||
Statistical analysis description |
ORR was evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 5% using an exact test of binomial distribution.
|
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Comparison groups |
PD-L1 TPS Positive Participants v Duplicate PD-L1 TPS Positive Participants
|
||||||||||||
Number of subjects included in analysis |
242
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [8] | ||||||||||||
Method |
exact binomial distribution | ||||||||||||
Confidence interval |
|||||||||||||
| Notes [8] - null hypothesis (H0): p ≤0.05 versus alternate hypothesis (H1): p >0.05 |
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End point title |
Objective Response Rate (ORR) by Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Strong Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||||||
End point description |
Participants with a strong positive PD-L1 expression status were evaluated for ORR by modified RECIST 1.1. PD-L1 expression was determined by IHC and strong PD-L1 positive was defined as a TPS ≥50%. ORR was assessed by imaging every 6-9 weeks after the first dose. ORR was defined as the percentage of participants who had a CR defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to <10 mm or PR defined as at least a 30% decrease in the SPD of target lesions, using the baseline SPD as a reference. If imaging shows PD imaging was repeated 4 weeks later for confirmation. PD was defined as ≥20% increase in the SPD of target lesions and new measurable lesions, taking as reference the smallest sum recorded since treatment started. Participants with missing data were considered non-responders. The analysis included all participants who received ≥1 dose of study treatment with a tumor proportion score ≥50%.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to 76.9 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ORR Comparison to Fixed Efficacy Target | ||||||||||||
Statistical analysis description |
ORR was evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 5% using an exact test of binomial distribution.
|
||||||||||||
Comparison groups |
Strong PD-L1 TPS Positive Participants v Duplicate Strong PD-L1 TPS Positive Participants
|
||||||||||||
Number of subjects included in analysis |
88
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [9] | ||||||||||||
Method |
exact binomial distribution | ||||||||||||
Confidence interval |
|||||||||||||
| Notes [9] - null hypothesis (H0): p ≤0.05 versus alternate hypothesis (H1): p >0.05 |
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|
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End point title |
Response Duration (DOR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants | ||||||||
End point description |
DOR was based on RECIST 1.1 and measured from the time of CR/PR (whichever was first recorded) until the first date that recurrent or PD was documented (taking as reference for PD the smallest measurements recorded on study). DOR was censored at the last tumor assessment date if a responder did not have PD or death. Non-responders were not included in the analysis. The lower and upper limits were estimated at the time of data cutoff. DOR was analyzed by the Kaplan-Meier method for censored data and reported in months. 9999=Upper limit not reached at time of data cut-off due to insufficient number of responding participants with relapse. The analysis included all participants who received ≥1 dose of study treatment with a best overall response as confirmed CR or PR.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 76.9 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Response Duration (DOR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||
End point description |
Participants with a positive PD-L1 expression status were evaluated for DOR based on RECIST 1.1. PD-L1 expression was determined by IHC and PD-L1 positive was defined as a PD-L1 combined positive score ≥1%. DOR was measured from the time of CR/PR (whichever was first recorded) until the first date that recurrent or PD was documented (taking as reference for PD the smallest measurements recorded on study). DOR was censored at the last tumor assessment date if a responder did not have PD or death. Non-responders were not included in the analysis. The lower and upper limits were estimated at the time of data cutoff. DOR was analyzed by the Kaplan-Meier method for censored data and reported in months. 9999=Upper limit not reached at time of data cut-off due to insufficient number of responding participants with relapse. The analysis included all participants who received ≥1 dose of study treatment with a combined positive score ≥1% and a best overall response as confirmed CR or PR.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 76.9 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Response Duration (DOR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Strong Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||
End point description |
Participants with a strong PD-L1 expression status were evaluated for DOR based n RECIST 1.1. PD-L1 expression was determined by IHC and strong PD-L1 positive was defined as a PD-L1 tumor proportion score ≥50%. DOR was measured from the of CR/PR (whichever was first recorded) until the first date that recurrent or PD was documented (taking as reference for PD the smallest measurements recorded on study). DOR was censored at the last tumor assessment date if a responder did not have PD or death. Non-responders were not included in the analysis. The lower and upper limits were estimated at the time of data cutoff. DOR was analyzed by the Kaplan-Meier method for censored data and reported in months. 9999=Upper limit not reached at time of data cut-off due to insufficient number of responding participants with relapse. The analysis included all participants who received ≥1dose of study treatment with a tumor proportion score ≥50% and a best overall response as confirmed CR or PR.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 76.9 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants | ||||||||
End point description |
PFS was defined as the time from the first day of study treatment to the first documented PD per RECIST 1.1 or death due to any cause, whichever occurred first. Using RECIST 1.1, PD was defined as either a 20% relative increase in the sum of diameters of target lesions, taking as reference the smallest sum on study OR an absolute increase of >5 mm the sum of lesions, OR the appearance of new lesions. PFS was analyzed by the Kaplan-Meier method for censored data and reported in months. Participant data were censored at last assessment. The analysis included all participants who received ≥1dose of study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 76.9 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||
End point description |
Participants with a positive PD-L1 expression status were evaluated for PFS. PD-L1 expression was determined by IHC and PD-L1 positive was defined as a PD-L1 combined positive score ≥1%. PFS was defined as the time from the first day of study treatment to the first documented PD per RECIST 1.1 or death due to any cause, whichever occurred first. Using RECIST 1.1, PD was defined as either a 20% relative increase in the sum of diameters of target lesions, taking as reference the smallest sum on study OR an absolute increase of >5 mm the sum of lesions, OR the appearance of new lesions. PFS was analyzed by the Kaplan-Meier method for censored data and reported in months. Participant data were censored at last assessment. The analysis included all participants who received ≥1 dose of study treatment with a combined positive score ≥1%.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 76.9 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Strong Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||
End point description |
Participants with a strong PD-L1 expression status were evaluated for PFS by modified RECIST 1.1. PD-L1 expression was determined by IHC and strong PD-L1 positive was defined as a PD-L1 tumor proportion score ≥50%. PFS was defined as the time from the first day of study treatment to the first documented PD per RECIST 1.1 or death due to any cause, whichever occurred first. Using RECIST 1.1, PD was defined as either a 20% relative increase in the sum of diameters of target lesions, taking as reference the smallest sum on study OR an absolute increase of >5 mm the sum of lesions, OR the appearance of new lesions. PFS was analyzed by the Kaplan-Meier method for censored data and reported in months. Participant data were censored at last assessment. The analysis included all participants who received ≥1 dose of study treatment with a tumor proportion score ≥50%.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 76.9 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Overall Survival (OS) in All Participants | ||||||||
End point description |
OS was defined as the time from the first day of study treatment to death due to any cause. OS was analyzed by the Kaplan-Meier method for censored data and reported in months. Participant data were censored at last assessment. The analysis included all participants who received ≥1dose of study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 76.9 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Overall Survival (OS) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||
End point description |
Participants with a positive PD-L1 expression status were evaluated for OS. PD-L1 expression was determined by IHC and PD-L1 positive was defined as a PD-L1 combined positive score ≥1%. OS was defined as the time from the first day of study treatment to death due to any cause. OS was analyzed by the Kaplan-Meier method for censored data and reported in months. Participant data were censored at last assessment. The analysis included all participants who received ≥1 dose of study treatment with a combined positive score ≥1%.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 76.9 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Overall Survival (OS) in Strong Programmed Cell Death Ligand 1 (PD-L1) Positive Participants | ||||||||
End point description |
Participants with a strong PD-L1 expression status were evaluated for OS. PD-L1 expression was determined by IHC and strong PD-L1 positive was defined as a PD-L1 tumor proportion score ≥50%. OS was defined as the time from the first day of study treatment to death due to any cause. OS was analyzed by the Kaplan-Meier method for censored data and reported in months. Participant data were censored at last assessment. The analysis included all participants who received ≥1dose of study treatment with a tumor proportion score ≥50%.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 76.9 months
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
|
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Timeframe for reporting adverse events |
First Course: Up to 76.9 months
Second Course: Up to 53.3 months
First and second course dosing occurred concurrently
|
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Adverse event reporting additional description |
All-cause mortality (ACM)=all allocated participants (n=172); AEs=all participants who received ≥1 dose of study treatment (n=171). Per protocol, Medical Dictionary for Regulatory Activities (MedDRA) terms neoplasm progression (NP), malignant NP, and disease progression not related to treatment were excluded.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
|
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Reporting groups
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Reporting group title |
Pembrolizumab Second Course
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Reporting group description |
Participants who met the criteria for retreatment received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 1 year of treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pembrolizumab First Course
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Reporting group description |
Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 24 months. Participants who stopped pembrolizumab as a result of obtaining a CR or those who stopped after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, were eligible for up to an additional 1 year of treatment after progressive disease if they met the criteria for re-treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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19 Dec 2014 |
Amendment 01 removed the option to discontinue pharmacokinetics (PK) sampling after the assessment of the first 65-70 participants and instituted PK analysis for all participants. In addition, language was added to clarify that PK samples will also be used to explore the exposure-response relationships for pembrolizumab and measures of anti-tumor activity/efficacy, toxicity, and pharmacodynamics in the proposed population of participants. |
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06 May 2015 |
Amendment 02 modified the objective response rate (ORR) endpoint to specify analyses in a Programmed Cell Death Ligand-1 (PD-L1) strong positive subgroup instead of any PD-L1 positivity. The analysis of any PD-L1 positivity is now a secondary objective. |
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22 Mar 2016 |
Amendment 03 unblinded the Sponsor to the PD-L1 data, after the cut-point for PD-L1 strong positive was determined, in support of the upcoming analyses. |
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08 Dec 2017 |
Amendment 04 revised the survival status activities to enable flexibility and ensure that current and complete survival data are available at the time of database locks. In addition, the dose modification guidelines were replaced to provide current comprehensive guidelines for management of immune-related adverse events associated with pembrolizumab. |
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04 Apr 2018 |
Amendment 05 made a correction to the trial diagram. |
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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 | |||
