Non-small Cell Lung Cancer
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Brief summary
This is a study of carboplatin and paclitaxel or nano particle albumin-bound paclitaxel (nab-paclitaxel) with or without pembrolizumab (MK-3475, KEYTRUDA®) in adults with first line metastatic squamous non-small cell lung cancer (NSCLC). The primary hypotheses are that treatment with pembrolizumab prolongs: 1) Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by a blinded central imaging vendor compared to placebo, and 2) Overall Survival (OS). After analysis of interim results was conducted, the protocol was amended (Amendment 5) to allow participants the option to discontinue placebo in the control arm and to switch to pembrolizumab in the event of documented progressive disease as assessed by central review.
Interventions
BIOLOGICALPembrolizumab
IV infusion
DRUGPaclitaxel
IV infusion
DRUGNab-paclitaxel
IV infusion
DRUGCarboplatin
IV infusion Carboplatin dose should not to exceed 900 mg.
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a histologically or cytologically confirmed diagnosis of stage IV (M1a or M1b-American Joint Committee on Cancer \[AJCC\] 7th edition) squamous NSCLC. * Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. * Has not received prior systemic treatment for metastatic NSCLC. * Has provided tumor tissue from locations not radiated prior to biopsy. * Has a life expectancy of at least 3 months. * Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status. * Has adequate organ function. * If female of childbearing potential, is willing to use an adequate method of contraception for the course of the study through 180 days after the last dose of study drug. * If male with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception starting with the first dose of study drug through 95 days after the last dose of study drug. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
Exclusion criteria
* Has non-squamous histology NSCLC. * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab. * Before the first dose of study drug: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease; b) Has received other targeted or biological antineoplastic therapy (e.g., erlotinib, crizotinib, cetuximab) for metastatic disease; c) Has had major surgery (\<3 weeks prior to first dose). * Received radiation therapy to the lung that is \> 30 Gy within 6 months of the first dose of study drug. * Completed palliative radiotherapy within 7 days of the first dose of study drug. * Is expected to require any other form of antineoplastic therapy while on study. * Has received a live-virus vaccination within 30 days of planned treatment start. * Has a known history of prior malignancy except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy. * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. * Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria. * Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody. * Has a known sensitivity to any component of carboplatin or paclitaxel or nab-paclitaxel. * Has active autoimmune disease that has required systemic treatment in past 2 years. * Is on chronic systemic steroids. * Had prior treatment with any other anti-programmed cell death 1 (anti-PD-1), or programmed cell death ligand 1 (PD-L1) or PD-L2 agent or an antibody or a small molecule targeting other immuno-regulatory receptors or mechanisms. * Has participated in any other pembrolizumab trial and has been treated with pembrolizumab. * Has an active infection requiring therapy. * Has known history of Human Immunodeficiency Virus (HIV). * Has known active Hepatitis B or C. Active Hepatitis B. * Is, at the time of providing documented informed consent, a regular user (including recreational use) of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol). * Has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 19 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. Per Response Criteria in Solid Tumors version 1.1 (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 ≥1 new lesions was also considered PD. PFS as assessed by blinded independent central review per RECIST 1.1 is presented. |
| Overall Survival (OS) | Up to approximately 19 months | OS was defined as the time from randomization to death due to any cause. OS is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 19 months | ORR was defined as the percentage of participants 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) as assessed by RECIST 1.1. ORR as assessed by blinded independent central review per RECIST 1.1 is presented. |
| Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Up to approximately 19 months | For participants who demonstrated a confirmed response (Complete Response \[CR\]: Disappearance of all target lesions or Partial Response \[PR\]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression as assessed by RECIST 1.1 or death. DOR as assessed by blinded independent central review per RECIST 1.1 is presented. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 83 months | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced an AE is presented. |
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | Up to approximately 29 months | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE was presented. |
Participant flow
Pre-assignment details
Per protocol, response/progression, or adverse events during the second and switch-over pembrolizumab course were not counted towards efficacy outcome measures or safety outcome measures.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Chemotherapy Combo Participants received pembrolizumab 200 mg by intravenous (IV) infusion prior to chemotherapy on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (\
2 years) PLUS Investigator's choice of paclitaxel (200 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) or nab-paclitaxel (100 mg/m\^2 by IV infusion on Days 1, 8, 15 of each 21-day cycle for 4 cycles) PLUS carboplatin Area Under Curve (AUC) 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles. Participants who received pembrolizumab 200 mg IV Day 1 of 21-day cycle for up to 2 years, but experienced disease progression, were eligible to receive a second course of pembrolizumab 200 mg IV Day 1 of 21-day cycle, at the investigator's discretion, for 17 cycles (\
1 year additional). | 278 |
| Placebo + Chemotherapy Participants received normal saline as placebo by IV infusion prior to chemotherapy on Day 1 of 21-day cycle for up to 35 cycles (\
2 years) PLUS Investigator's choice of paclitaxel (200 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) or nab-paclitaxel (100 mg/m\^2 by IV infusion on Days 1, 8, 15 of each 21-day cycle for 4 cycles) PLUS carboplatin AUC 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles. Participants with documented disease progression following placebo chemotherapy combo could switch-over to receive pembrolizumab for up to 35 cycles (\
2 years). Eligible cross over participants who stopped pembrolizumab and had stable disease but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion for up to 17 cycles (\
1 year additional). | 281 |
| Total | 559 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 32 | 27 |
| Overall Study | Death | 196 | 224 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Sponsor decision | 44 | 19 |
| Overall Study | Withdrawal by Subject | 4 | 9 |
Baseline characteristics
| Characteristic | Pembrolizumab + Chemotherapy Combo | Total | Placebo + Chemotherapy |
|---|---|---|---|
| Age, Continuous | 65.0 Years STANDARD_DEVIATION 8.8 | 64.9 Years STANDARD_DEVIATION 8.7 | 64.8 Years STANDARD_DEVIATION 8.7 |
| Geographic Region East Asia | 54 Participants | 106 Participants | 52 Participants |
| Geographic Region Non-East Asia | 224 Participants | 453 Participants | 229 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Level: Tumor Proportion Score (TPS) TPS <1% | 95 Participants | 194 Participants | 99 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Level: Tumor Proportion Score (TPS) TPS ≥1% | 176 Participants | 353 Participants | 177 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Level: Tumor Proportion Score (TPS) Unknown | 7 Participants | 12 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 56 Participants | 108 Participants | 52 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 11 Participants | 9 Participants |
| Race (NIH/OMB) White | 216 Participants | 430 Participants | 214 Participants |
| Sex: Female, Male Female | 58 Participants | 104 Participants | 46 Participants |
| Sex: Female, Male Male | 220 Participants | 455 Participants | 235 Participants |
| Taxane Chemotherapy +Nab-paclitaxel | 109 Participants | 223 Participants | 114 Participants |
| Taxane Chemotherapy +Paclitaxel | 169 Participants | 336 Participants | 167 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 225 / 278 | 143 / 281 | 111 / 118 | 6 / 12 | 0 / 1 |
| other Total, other adverse events | 270 / 278 | 272 / 280 | 90 / 118 | 9 / 12 | 0 / 1 |
| serious Total, serious adverse events | 128 / 278 | 114 / 280 | 35 / 118 | 2 / 12 | 0 / 1 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. OS is presented.
Time frame: Up to approximately 19 months
Population: The Intent-To-Treat population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment arm to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy Combo | Overall Survival (OS) | 15.9 Months |
| Placebo + Chemotherapy | Overall Survival (OS) | 11.3 Months |
p-value: 0.000895% CI: [0.49, 0.85]Regression, Cox
Primary
Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (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 ≥1 new lesions was also considered PD. PFS as assessed by blinded independent central review per RECIST 1.1 is presented.
Time frame: Up to approximately 19 months
Population: The Intent-To-Treat population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment arm to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy Combo | Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 6.4 Months |
| Placebo + Chemotherapy | Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 4.8 Months |
p-value: <0.000195% CI: [0.45, 0.7]Regression, Cox
Secondary
Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
For participants who demonstrated a confirmed response (Complete Response \[CR\]: Disappearance of all target lesions or Partial Response \[PR\]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression as assessed by RECIST 1.1 or death. DOR as assessed by blinded independent central review per RECIST 1.1 is presented.
Time frame: Up to approximately 19 months
Population: The Intent-To-Treat population consisted of all randomized participants, regardless of whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy Combo | Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 7.7 Months |
| Placebo + Chemotherapy | Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 4.8 Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE was presented.
Time frame: Up to approximately 29 months
Population: The Safety population consisted of all participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Chemotherapy Combo | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 80 Participants |
| Placebo + Chemotherapy | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 37 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced an AE is presented.
Time frame: Up to approximately 83 months
Population: The Safety population consisted of all participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Chemotherapy Combo | Number of Participants Who Experienced an Adverse Event (AE) | 274 Participants |
| Placebo + Chemotherapy | Number of Participants Who Experienced an Adverse Event (AE) | 275 Participants |
Secondary
Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
ORR was defined as the percentage of participants 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) as assessed by RECIST 1.1. ORR as assessed by blinded independent central review per RECIST 1.1 is presented.
Time frame: Up to approximately 19 months
Population: The Intent-To-Treat population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment arm to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Chemotherapy Combo | Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 57.9 Percentage of Participants |
| Placebo + Chemotherapy | Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 38.4 Percentage of Participants |