Small Cell Lung Cancer (SCLC)
Conditions
Keywords
Extensive stage small cell lung cancer (ES-SCLC), Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death Ligand 1 (PDL1, PD-L1), Programmed Cell Death Ligand 2 (PDL2, PD-L2)
Brief summary
The purpose of this study is to assess the safety and efficacy of pembrolizumab plus standard of care (SOC) chemotherapy (etoposide/platinum \[EP\]) in participants with newly diagnosed extensive stage small cell lung cancer (ES-SCLC) who have not previously received systemic therapy for this malignancy. The primary study hypotheses are that pembrolizumab+EP prolongs Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review (BICR) and Overall Survival (OS) compared with placebo+EP in adult participants with ES-SCLC. In this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. With protocol Amendment 07 (03-Oct-2018), the outcome measure of Change from Baseline at Weeks 12 and 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale was replaced with a single time point analysis at Week 18.
Interventions
BIOLOGICALPembrolizumab
IV infusion on Day 1 of each cycle prior to chemotherapy
DRUGNormal saline solution
IV infusion on Day 1 of each cycle prior to chemotherapy
DRUGCarboplatin
IV infusion on Day 1 of each cycle
DRUGCisplatin
IV infusion on Day 1 of each cycle
DRUGEtoposide
IV infusion on Days 1, 2 and 3 of each cycle
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a documented new diagnosis of SCLC by histology or cytology from brushing, washing, or needle aspiration of a defined lesion. Participants who do not have histology samples (defined as core or excisional biopsy, or resections) will need to undergo a new biopsy to provide a tissue sample. * Has extensive-stage disease defined as Stage IV (T any, N any, M 1a/b) by the American Joint Committee on Cancer (AJCC), Seventh Edition * Has ≥1 lesion that meets the criteria for measurable, as defined by RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local site investigator/radiology assessment * Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated * Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Has a life expectancy of ≥3 months * Has adequate organ function * Female and male participants of childbearing potential must be willing to use an adequate method of contraception, starting with the first dose of study treatment through 120 days after the last dose of study treatment and up to 180 days after last dose of chemotherapeutic agents
Exclusion criteria
* Has received prior systemic therapy for the treatment of SCLC * Is currently participating and receiving study treatment or has participated in a study of an investigational agent and received study treatment or used an investigational device within 4 weeks of the first dose of treatment for another health-related problem * Is expected to require any other form of antineoplastic therapy for SCLC, including radiation therapy, while on study. (Prophylactic cranial irradiation will be possible for those participants with stable disease or better at the completion of the 4 cycles of chemotherapy with or without pembrolizumab.) * Has known central nervous system (ie, brain and/or spinal cord) metastases and/or carcinomatous meningitis. Participants with brain metastases may participate only if they satisfy all of the following: * Has completed treatment (eg, whole brain radiation treatment \[WBRT\], stereotactic radiosurgery, or equivalent) ≥14 days prior to the first dose of study treatment, * Has no evidence of new or enlarging brain metastases confirmed by post-treatment repeat brain imaging performed ≥3 weeks after pre-treatment brain imaging, and * Is neurologically stable without the need for steroids for ≥7 days before first dose of study treatment. * Has had major surgery within 3 weeks prior to receiving the first dose of study treatment or has not recovered adequately from toxicity and/or complications from an intervention prior to receiving the first dose of study treatment. * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has a known history of interstitial lung disease * Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy. * Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment. * Has a known history of, or active, neurologic paraneoplastic syndrome * Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, and/or abdominal carcinomatosis * Has a history of a severe hypersensitivity reaction to treatment with another monoclonal antibody * Is taking chronic systemic steroids (in doses exceeding 10 mg daily of prednisone equivalent) within 7 days prior to the first dose of study treatment * Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of study treatment * Has received a live vaccine within 30 days prior to the first dose of study treatment * Has received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti-PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor (i.e., cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], tumor necrosis factor receptor superfamily member 9 \[TNFRSF9, OX-40, CD137\]) or has previously participated in a Merck pembrolizumab (MK-3475) clinical trial * Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients * Has an active infection requiring systemic therapy * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of Hepatitis B or known active Hepatitis C virus infection * Has a known history of active TB (Bacillus Tuberculosis) * Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study starting with the screening visit through 120 days after the last dose of study treatment through and up to 180 days after last dose of chemotherapeutic agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 30.5 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD, as determined by RECIST 1.1, was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. For this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The PFS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol. |
| Overall Survival (OS) | Up to approximately 30.5 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow up. The OS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 30.5 months | An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who experienced an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol. |
| Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE) | Up to approximately 26 months | An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who discontinued due to an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol. |
| Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03) | Up to approximately 30.5 months | The CTCAE uses Grades 1 through 5 correlating to AE severity criteria. Grade 1=mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2=moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3=severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4=life-threatening consequences; urgent intervention indicated. Grade 5=death related to AE. The number of participants who experienced any Grade 3 to 5 AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol. |
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 30.5 months | ORR was defined as the percentage of participants who achieve a best objective response of complete response (CR) or partial response (PR) per RECIST 1.1. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The ORR was calculated using the Miettinen & Nurminen method stratified by type of platinum therapy (carboplatin or cisplatin), baseline ECOG performance status (0 or 1), and baseline LDH (≤ or \> upper limit of normal) and presented for the first course of study treatment per protocol. |
| Change From Baseline at Week 12 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 12 | EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment. |
| Change From Baseline at Week 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 24 | EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment. |
| Time to True Deterioration (TTD) in the Composite Endpoint of Cough, Chest Pain, and Dyspnea Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13) | Day 1 of Cycles 1-9, Day 1 of every other cycle for Cycles 10-17 and 30 days after last dose of study treatment (Up to approximately 27 months) | TTD in patient-reported lung cancer symptoms of cough (QLQ-LC-13 Item 1), chest pain (QLQ-LC-13 Item 10), and dyspnea (QLQ-C30 Item 8) was a composite endpoint defined as the time to first onset of ≥10 point deterioration from baseline in an item confirmed by a second adjacent ≥10 point deterioration. The QLQ-LC13 consists of 13 measures of lung cancer symptoms and side effects from chemotherapy and radiation. It is scored on a 4-point scale (1=none, 2=a little, 3=quite a bit, 4=very much). Scores were transformed to a range of 0 to 100 using a standard algorithm. Higher scores represented increasing symptom severity. TTD was calculated using the product-limit Kaplan-Meier method for censored data and is presented for the first course of study treatment per protocol. |
| Change From Baseline at Week 18 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 18 | EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. Change from baseline scores were calculated using a constrained longitudinal data analysis (cLDA) model. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Data are presented for the first course of study treatment per protocol. |
| Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 30.5 months | DOR was defined as the time from first documented evidence of a Complete Response (CR) or Partial Response (PR) per RECIST 1.1 until progressive disease (PD) per RECIST 1.1 or death due to any cause, whichever occurred first. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data and is presented for the first course of study treatment per protocol. |
Countries
Australia, Canada, Chile, France, Germany, Hungary, Ireland, Israel, Japan, New Zealand, Poland, Russia, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants in the pembrolizumab+ chemotherapy (etoposide/platinum \[EP\]) arm were eligible to receive second course treatment with pembrolizumab if they met criteria for re-treatment. Per protocol, response, progression, or patient reported outcomes during the second course were not counted towards efficacy outcome measures and adverse events during the second course were not counted towards safety outcome measures.
Pre-assignment details
One participant who was randomized to the pembrolizumab+EP arm was inadvertently treated with placebo+EP. For efficacy analyses this participant will be included in the arm they were initially randomized into and for safety analyses the participant will be included by treatment received.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab+EP During each 21-day cycle, participants received pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m\^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve \[AUC\] 5 IV on Day 1 OR cisplatin 75 mg/m\^2 IV on Day 1). Participants who stopped pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (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. | 228 |
| Placebo+EP During each 21-day cycle, participants received placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m\^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m\^2 IV on Day 1). | 225 |
| Total | 453 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 195 | 205 |
| Overall Study | Withdrawal by Subject | 5 | 7 |
Baseline characteristics
| Characteristic | Pembrolizumab+EP | Placebo+EP | Total |
|---|---|---|---|
| Age, Continuous | 64.2 Years STANDARD_DEVIATION 8.4 | 65.2 Years STANDARD_DEVIATION 8.2 | 64.7 Years STANDARD_DEVIATION 8.3 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG = 0 | 60 Participants | 56 Participants | 116 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG = 1 | 168 Participants | 169 Participants | 337 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 13 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 204 Participants | 192 Participants | 396 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 20 Participants | 38 Participants |
| Lactate Dehydrogenase (LDH) Status at Baseline LDH Result Missing | 1 Participants | 1 Participants | 2 Participants |
| Lactate Dehydrogenase (LDH) Status at Baseline LDH = ≤ Upper Limit of Normal | 100 Participants | 95 Participants | 195 Participants |
| Lactate Dehydrogenase (LDH) Status at Baseline LDH = > Upper Limit of Normal | 127 Participants | 129 Participants | 256 Participants |
| Platinum Therapy Administered Carboplatin | 161 Participants | 156 Participants | 317 Participants |
| Platinum Therapy Administered Cisplatin | 63 Participants | 66 Participants | 129 Participants |
| Platinum Therapy Administered Not Treated with Platinum Therapy | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 52 Participants | 34 Participants | 86 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 13 Participants | 26 Participants |
| Race (NIH/OMB) White | 162 Participants | 177 Participants | 339 Participants |
| Sex: Female, Male Female | 76 Participants | 83 Participants | 159 Participants |
| Sex: Female, Male Male | 152 Participants | 142 Participants | 294 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 196 / 227 | 212 / 226 | 1 / 1 |
| other Total, other adverse events | 221 / 223 | 216 / 223 | 1 / 1 |
| serious Total, serious adverse events | 111 / 223 | 89 / 223 | 1 / 1 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow up. The OS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol.
Time frame: Up to approximately 30.5 months
Population: The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+EP | Overall Survival (OS) | 10.8 Months |
| Placebo+EP | Overall Survival (OS) | 9.7 Months |
p-value: 0.0164395% CI: [0.64, 0.98]Log Rank
Primary
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD, as determined by RECIST 1.1, was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. For this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The PFS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol.
Time frame: Up to approximately 30.5 months
Population: The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+EP | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 4.8 Months |
| Placebo+EP | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 4.3 Months |
p-value: 0.0006995% CI: [0.6, 0.88]Log Rank
Secondary
Change From Baseline at Week 12 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale
EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment.
Time frame: Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 12
Population: All participants who received at least 1 dose of study medication and had non-missing assessments at baseline and Week 12. This outcome measure was replaced with a single time-point analysis at Week 18 as pre-specified with Amendment 7 of the protocol (03-Oct-2018).
Secondary
Change From Baseline at Week 18 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale
EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. Change from baseline scores were calculated using a constrained longitudinal data analysis (cLDA) model. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Data are presented for the first course of study treatment per protocol.
Time frame: Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 18
Population: All participants who received at least 1 dose of study medication and had non-missing assessments at baseline and Week 18.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab+EP | Change From Baseline at Week 18 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale | 8.66 Score on a Scale |
| Placebo+EP | Change From Baseline at Week 18 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale | 4.23 Score on a Scale |
p-value: 0.0495% CI: [0.21, 8.66]Log Rank
Secondary
Change From Baseline at Week 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale
EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment.
Time frame: Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 24
Population: All participants who received at least 1 dose of study medication and had non-missing assessments at baseline and Week 24. This outcome measure was replaced with a single time-point analysis at Week 18 as pre-specified with Amendment 7 of the protocol (03-Oct-2018).
Secondary
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
DOR was defined as the time from first documented evidence of a Complete Response (CR) or Partial Response (PR) per RECIST 1.1 until progressive disease (PD) per RECIST 1.1 or death due to any cause, whichever occurred first. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data and is presented for the first course of study treatment per protocol.
Time frame: Up to approximately 30.5 months
Population: The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized and experienced a CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+EP | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | NA Months |
| Placebo+EP | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | NA Months |
Secondary
Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE)
An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who discontinued due to an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.
Time frame: Up to approximately 26 months
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab+EP | Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE) | 33 Participants |
| Placebo+EP | Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE) | 14 Participants |
Secondary
Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03)
The CTCAE uses Grades 1 through 5 correlating to AE severity criteria. Grade 1=mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2=moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3=severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4=life-threatening consequences; urgent intervention indicated. Grade 5=death related to AE. The number of participants who experienced any Grade 3 to 5 AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.
Time frame: Up to approximately 30.5 months
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab+EP | Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03) | 175 Participants |
| Placebo+EP | Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03) | 172 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who experienced an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.
Time frame: Up to approximately 30.5 months
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab+EP | Number of Participants Who Experienced an Adverse Event (AE) | 223 Participants |
| Placebo+EP | Number of Participants Who Experienced an Adverse Event (AE) | 222 Participants |
Secondary
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
ORR was defined as the percentage of participants who achieve a best objective response of complete response (CR) or partial response (PR) per RECIST 1.1. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The ORR was calculated using the Miettinen & Nurminen method stratified by type of platinum therapy (carboplatin or cisplatin), baseline ECOG performance status (0 or 1), and baseline LDH (≤ or \> upper limit of normal) and presented for the first course of study treatment per protocol.
Time frame: Up to approximately 30.5 months
Population: The analysis population consisted of all randomized participants who were included in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+EP | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 70.6 Percentage of Participants |
| Placebo+EP | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 61.8 Percentage of Participants |
p-value: 0.022795% CI: [0.2, 17.4]Miettinen & Nurminen
Secondary
Time to True Deterioration (TTD) in the Composite Endpoint of Cough, Chest Pain, and Dyspnea Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13)
TTD in patient-reported lung cancer symptoms of cough (QLQ-LC-13 Item 1), chest pain (QLQ-LC-13 Item 10), and dyspnea (QLQ-C30 Item 8) was a composite endpoint defined as the time to first onset of ≥10 point deterioration from baseline in an item confirmed by a second adjacent ≥10 point deterioration. The QLQ-LC13 consists of 13 measures of lung cancer symptoms and side effects from chemotherapy and radiation. It is scored on a 4-point scale (1=none, 2=a little, 3=quite a bit, 4=very much). Scores were transformed to a range of 0 to 100 using a standard algorithm. Higher scores represented increasing symptom severity. TTD was calculated using the product-limit Kaplan-Meier method for censored data and is presented for the first course of study treatment per protocol.
Time frame: Day 1 of Cycles 1-9, Day 1 of every other cycle for Cycles 10-17 and 30 days after last dose of study treatment (Up to approximately 27 months)
Population: All participants who received at least 1 dose of study medication and had non-missing assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+EP | Time to True Deterioration (TTD) in the Composite Endpoint of Cough, Chest Pain, and Dyspnea Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13) | NA Months |
| Placebo+EP | Time to True Deterioration (TTD) in the Composite Endpoint of Cough, Chest Pain, and Dyspnea Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13) | 8.7 Months |
p-value: 0.20895% CI: [0.56, 1.14]Log Rank