Head and Neck Squamous Cell Cancer
Conditions
Keywords
Squamous cell carcinoma, Head and neck carcinoma, Programmed Cell Death-1 (PD1, PD-1),, Programmed Death-Ligand 1 (PDL1, PD-L1), Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)
Brief summary
This is a study of pembrolizumab (MK-3475, KEYTRUDA®) versus standard treatment (methotrexate, docetaxel or cetuximab) for the treatment of recurrent or metastatic head and neck squamous cell cancer (HNSCC). Participants will be randomly assigned to receive either pembrolizumab or Investigator's choice of standard treatment. The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment.
Interventions
BIOLOGICALPembrolizumab
200 mg intravenous (IV) on Day 1 of each 3-week cycle.
DRUGMethotrexate
40 mg/m\^2 IV (may be escalated to 60 mg/m\^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle
DRUGDocetaxel
75 mg/m\^2 IV on Day 1 of each 3- week cycle
BIOLOGICALCetuximab
400 mg/m\^2 IV loading dose on Day 1 and 250 mg/m\^2 IV on Days 8 and 15 of Cycle 1, followed by 250 mg/m\^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically- or cytologically-confirmed recurrent disease not amenable to curative treatment with local or systemic therapy, or metastatic (disseminated) head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies * Failure of prior platinum therapy * Radiographically-measurable disease based on RECIST 1.1 * Tumor tissue available for PD-L1 biomarker analysis * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate organ function * Female participants of childbearing potential must be willing to use 2 methods of birth control or abstain from heterosexual activity for the course of the study through 120 days after last dose of pembrolizumab or through 120-180 days after the last dose of docetaxel, methotrexate or cetuximab, acccording to local standard of care * Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after last dose of pembrolizumab or through 120-180 days after the last dose of docetaxel, methotrexate or cetuximab, acccording to local standard of care
Exclusion criteria
* Disease is suitable for local therapy administered with curative intent * Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to randomization * Previously treated with 3 or more systemic regimens given for recurrent and/or metastatic disease * Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study therapy * Not recovered from adverse events due to therapy more than 4 weeks earlier * Prior anti-cancer monoclonal antibody (mAb) therapy within 4 weeks prior to study Day 1, or not recovered from adverse events due to agents administered more than 4 weeks earlier * Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 * Diagnosed and/or treated additional malignancy within 5 years of randomization, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin, and/or curatively-resected in situ cervical and/or breast cancers * Active autoimmune disease that has required systemic therapy in the past 2 years with modifying agents, corticosteroids, or immunosuppressive agents * Active central nervous system (CNS) metastases and/or carcinomatous meningitis * Active, non-infectious pneumonitis * Active infection requiring systemic therapy * Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial therapy according to local standard of care * Prior therapy with an anti-PD-1 or anti-PD1-L1 or -L2 therapy or previously participated in a Merck pembrolizumab (MK-3475) trial * Human immunodeficiency virus (HIV) * Hepatitis B or C * Live vaccine within 30 days of planned start of study therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Initial Overall Survival (OS) for All Participants | Up to approximately 2 years | 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 to be censored at the date of the last follow-up. The OS for all participants is presented. These initial OS results are based on a data cutoff date of 15-May-2017 with a database lock date of 04-Jun-2017. At the time of the database lock of 04-Jun-2017, there was incomplete collection of survival data for 12 participants. |
| Updated Final OS for All Participants | Up to approximately 2 years | 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 to be censored at the date of the last follow-up. The updated OS for all participants is presented. These OS results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | Up to approximately 2 years | PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The PFS per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| Objective Response Rate (ORR) Per RECIST 1.1 in All Participants | Up to approximately 2 years | ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based on blinded central imaging vendor review with or without confirmation. The ORR per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| ORR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | Up to approximately 2 years | ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1 based on blinded central imaging vendor review with or without confirmation. The ORR per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| Duration of Response (DOR) Per RECIST 1.1 in All Participants | Up to approximately 2 years | For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from first documented evidence of a confirmed CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. DOR assessments were based on blinded central imaging vendor review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| DOR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | Up to approximately 2 years | For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from first documented evidence of a confirmed CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. DOR assessments were based on blinded central imaging vendor review with confirmation. The DOR per RECIST 1.1 for all participants with PD-L1 ≥1% CPS who experienced a confirmed CR or PR is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| Time to Progression (TTP) Per RECIST 1.1 in All Participants | Up to approximately 2 years | TTP was defined as the time from randomization to the first documented disease progression based on assessments by the blinded central imaging vendor review per RECIST 1.1. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The TTP per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| OS for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Expression Defined by ≥1% Combined Positive Score (CPS)(PD-L1 ≥1% CPS) | Up to approximately 2 years | 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. The OS for all participants with PD-L1 expression ≥1% CPS was presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| PFS Per Modified RECIST in All Participants | Up to approximately 2 years | PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. Modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (\>4 weeks after the initial PD) is required for participants who remain on treatment following a documented PD per RECIST 1.1. The PFS per modified RECIST for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| PFS Per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS | Up to approximately 2 years | PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. Modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (\>4 weeks after the initial PD) is required for participants who remain on treatment following a documented PD per RECIST 1.1. The PFS per modified RECIST for all participants with PD-L1 ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| Number of Participants Who Experienced At Least One Adverse Event (AE) in All Participants | Up to approximately 33 months | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants who experienced at least one AE is presented. |
| Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS | Up to approximately 33 months | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants with PD-L1 ≥1% CPS who experienced at least one AE is presented. |
| Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants | Up to approximately 30 months | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants who discontinued study treatment due to an AE is presented. |
| Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS | Up to approximately 30 months | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants with PD-L1 ≥1% CPS who discontinued study treatment due to an AE is presented. |
| TTP Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | Up to approximately 2 years | TTP was defined as the time from randomization to the first documented disease progression based on assessments by the blinded central imaging vendor review per RECIST 1.1. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The TTP per RECIST 1.1 for all participants with PD-L1 ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants | Up to approximately 2 years | PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The PFS per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017. |
Participant flow
Pre-assignment details
495 participants were randomized 1:1 to receive either pembrolizumab or standard treatment. Per protocol, response/progression or adverse events (AEs) that occurred during the second course of pembrolizumab were not counted towards efficacy outcome measures or safety outcome measures, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Participants received pembrolizumab 200 mg intravenous (IV) on Day 1 of each 3-week cycle. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion. | 247 |
| Standard Treatment Participants received standard treatment of either methotrexate 40 mg/m\^2 IV (could be escalated to 60 mg/m\^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m\^2 IV on Day 1 of each 3- week cycle; or cetuximab 400 mg/m\^2 IV loading dose on Day 1 and 250 mg/m\^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m\^2 on Days 1, 8, and 15 of each subsequent 3-week cycle. | 248 |
| Total | 495 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 6 |
| Overall Study | Death | 209 | 217 |
| Overall Study | Did Not Continue on Extension Study | 7 | 2 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Transferred to Extension Study | 7 | 1 |
| Overall Study | Withdrawal by Subject | 15 | 20 |
Baseline characteristics
| Characteristic | Pembrolizumab | Standard Treatment | Total |
|---|---|---|---|
| Age, Continuous | 60.3 Years STANDARD_DEVIATION 9.8 | 60.2 Years STANDARD_DEVIATION 8.6 | 60.2 Years STANDARD_DEVIATION 9.2 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS=1 | 176 Participants | 179 Participants | 355 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS=2 | 0 Participants | 1 Participants | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) EGOG PS=0 | 71 Participants | 68 Participants | 139 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 21 Participants | 12 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 182 Participants | 195 Participants | 377 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 44 Participants | 41 Participants | 85 Participants |
| Human Papillomavirus (HPV) Tumor Status Negative HPV Status | 186 Participants | 191 Participants | 377 Participants |
| Human Papillomavirus (HPV) Tumor Status Positive HPV Status | 61 Participants | 57 Participants | 118 Participants |
| PD-L1 Combined Positive Score (CPS) Status Missing | 1 Participants | 3 Participants | 4 Participants |
| PD-L1 Combined Positive Score (CPS) Status PD-L1 CPS <1 | 50 Participants | 54 Participants | 104 Participants |
| PD-L1 Combined Positive Score (CPS) Status PD-L1 CPS ≥1 | 196 Participants | 191 Participants | 387 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Expression Level: Tumor Proportion Score (TPS) 1% ≤ TPS <50% | 79 Participants | 87 Participants | 166 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Expression Level: Tumor Proportion Score (TPS) Missing | 1 Participants | 3 Participants | 4 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Expression Level: Tumor Proportion Score (TPS) TPS = 0% | 103 Participants | 93 Participants | 196 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Expression Level: Tumor Proportion Score (TPS) TPS ≥ 50% | 64 Participants | 65 Participants | 129 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 16 Participants | 31 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 7 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants | 15 Participants | 32 Participants |
| Race (NIH/OMB) White | 206 Participants | 207 Participants | 413 Participants |
| Sex: Female, Male Female | 40 Participants | 43 Participants | 83 Participants |
| Sex: Female, Male Male | 207 Participants | 205 Participants | 412 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 228 / 247 | 243 / 248 | 2 / 2 |
| other Total, other adverse events | 215 / 246 | 211 / 234 | 0 / 2 |
| serious Total, serious adverse events | 110 / 246 | 92 / 234 | 0 / 2 |
Outcome results
Primary
Initial Overall Survival (OS) for All Participants
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. The OS for all participants is presented. These initial OS results are based on a data cutoff date of 15-May-2017 with a database lock date of 04-Jun-2017. At the time of the database lock of 04-Jun-2017, there was incomplete collection of survival data for 12 participants.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Initial Overall Survival (OS) for All Participants | 8.4 Months |
| Standard Treatment | Initial Overall Survival (OS) for All Participants | 7.1 Months |
p-value: 0.031695% CI: [0.67, 1.01]Log Rank
Primary
Updated Final OS for All Participants
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. The updated OS for all participants is presented. These OS results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Updated Final OS for All Participants | 8.4 Months |
| Standard Treatment | Updated Final OS for All Participants | 6.9 Months |
p-value: 0.0160595% CI: [0.65, 0.98]Log Rank
Secondary
DOR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from first documented evidence of a confirmed CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. DOR assessments were based on blinded central imaging vendor review with confirmation. The DOR per RECIST 1.1 for all participants with PD-L1 ≥1% CPS who experienced a confirmed CR or PR is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS who demonstrated a confirmed CR or PR per RECIST 1.1. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | DOR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 18.4 Months |
| Standard Treatment | DOR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 9.6 Months |
Secondary
Duration of Response (DOR) Per RECIST 1.1 in All Participants
For participants who demonstrated a confirmed CR or PR per RECIST 1.1, DOR was defined as the time from first documented evidence of a confirmed CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. DOR assessments were based on blinded central imaging vendor review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants who demonstrated a confirmed CR or PR per RECIST 1.1. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Duration of Response (DOR) Per RECIST 1.1 in All Participants | 18.4 Months |
| Standard Treatment | Duration of Response (DOR) Per RECIST 1.1 in All Participants | 5.0 Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants who discontinued study treatment due to an AE is presented.
Time frame: Up to approximately 30 months
Population: The safety population consisted of all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants | 30 Participants |
| Standard Treatment | Number of Participants Who Discontinued Study Treatment Due to an AE in All Participants | 36 Participants |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants with PD-L1 ≥1% CPS who discontinued study treatment due to an AE is presented.
Time frame: Up to approximately 30 months
Population: The safety population consisted of all randomized participants with PD-L1 ≥1% CPS who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS | 25 Participants |
| Standard Treatment | Number of Participants Who Discontinued Study Treatment Due to an AE in Participants With PD-L1 ≥1% CPS | 29 Participants |
Secondary
Number of Participants Who Experienced At Least One Adverse Event (AE) in All Participants
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants who experienced at least one AE is presented.
Time frame: Up to approximately 33 months
Population: The safety population consisted of all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Experienced At Least One Adverse Event (AE) in All Participants | 240 Participants |
| Standard Treatment | Number of Participants Who Experienced At Least One Adverse Event (AE) in All Participants | 227 Participants |
Secondary
Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of all participants with PD-L1 ≥1% CPS who experienced at least one AE is presented.
Time frame: Up to approximately 33 months
Population: The safety population consisted of all randomized participants with PD-L1 ≥1% CPS who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS | 193 Participants |
| Standard Treatment | Number of Participants Who Experienced At Least One AE in Participants With PD-L1 ≥1% CPS | 178 Participants |
Secondary
Objective Response Rate (ORR) Per RECIST 1.1 in All Participants
ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based on blinded central imaging vendor review with or without confirmation. The ORR per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Objective Response Rate (ORR) Per RECIST 1.1 in All Participants | 14.6 Percentage of Participants |
| Standard Treatment | Objective Response Rate (ORR) Per RECIST 1.1 in All Participants | 10.1 Percentage of Participants |
p-value: 0.06195% CI: [-1.2, 10.6]Log Rank
Secondary
ORR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1 based on blinded central imaging vendor review with or without confirmation. The ORR per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | ORR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 17.3 Percentage of Participants |
| Standard Treatment | ORR Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 9.9 Percentage of Participants |
p-value: 0.017195% CI: [0.6, 14.6]Log Rank
Secondary
OS for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Expression Defined by ≥1% Combined Positive Score (CPS)(PD-L1 ≥1% CPS)
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. The OS for all participants with PD-L1 expression ≥1% CPS was presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | OS for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Expression Defined by ≥1% Combined Positive Score (CPS)(PD-L1 ≥1% CPS) | 8.7 Months |
| Standard Treatment | OS for Participants With Programmed Cell Death-Ligand 1 (PD-L1)-Positive Expression Defined by ≥1% Combined Positive Score (CPS)(PD-L1 ≥1% CPS) | 7.1 Months |
p-value: 0.0049395% CI: [0.58, 0.93]Log Rank
Secondary
PFS Per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. Modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (\>4 weeks after the initial PD) is required for participants who remain on treatment following a documented PD per RECIST 1.1. The PFS per modified RECIST for all participants with PD-L1 ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | PFS Per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 3.6 Months |
| Standard Treatment | PFS Per Modified RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 4.8 Months |
p-value: 0.5198295% CI: [0.81, 1.26]Log Rank
Secondary
PFS Per Modified RECIST in All Participants
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. Modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (\>4 weeks after the initial PD) is required for participants who remain on treatment following a documented PD per RECIST 1.1. The PFS per modified RECIST for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | PFS Per Modified RECIST in All Participants | 3.5 Months |
| Standard Treatment | PFS Per Modified RECIST in All Participants | 4.8 Months |
p-value: 0.6575995% CI: [0.86, 1.27]Log Rank
Secondary
PFS Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The PFS per RECIST 1.1 for all participants with PD-L1 expression ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | PFS Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 2.2 Months |
| Standard Treatment | PFS Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 2.3 Months |
p-value: 0.0773695% CI: [0.69, 1.06]Log Rank
Secondary
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants
PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The PFS per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants | 2.1 Months |
| Standard Treatment | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for All Participants | 2.3 Months |
p-value: 0.3250495% CI: [0.79, 1.16]Log Rank
Secondary
Time to Progression (TTP) Per RECIST 1.1 in All Participants
TTP was defined as the time from randomization to the first documented disease progression based on assessments by the blinded central imaging vendor review per RECIST 1.1. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The TTP per RECIST 1.1 for all participants is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Time to Progression (TTP) Per RECIST 1.1 in All Participants | 2.2 Months |
| Standard Treatment | Time to Progression (TTP) Per RECIST 1.1 in All Participants | 2.2 Months |
p-value: 0.1454595% CI: [0.7, 1.12]Log Rank
Secondary
TTP Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS
TTP was defined as the time from randomization to the first documented disease progression based on assessments by the blinded central imaging vendor review per RECIST 1.1. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression. The TTP per RECIST 1.1 for all participants with PD-L1 ≥1% CPS is presented. These efficacy results were reported after complete acquisition of all outstanding survival data using a 15-May-2017 data cut-off date with a database update date of 13-Oct-2017.
Time frame: Up to approximately 2 years
Population: The efficacy population consisted of all randomized participants with PD-L1 ≥1% CPS. Participants are included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | TTP Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 2.7 Months |
| Standard Treatment | TTP Per RECIST 1.1 in Participants With PD-L1 ≥1% CPS | 2.3 Months |
p-value: 0.0585195% CI: [0.62, 1.06]Log Rank