Non-Small-Cell Lung Carcinoma
Conditions
Keywords
PD1, PD-1, PDL1, PD-L1, Non-Small-Cell Lung Cancer
Brief summary
This is an efficacy and safety study of pembrolizumab (MK-3475) combined with pemetrexed/platinum chemotherapy versus pemetrexed/platinum chemotherapy alone in participants with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have not previously received systemic therapy for advanced disease. Participants will be randomly assigned to receive pembrolizumab combined with pemetrexed/platinum (Investigators choice of cisplatin or carboplatin), OR pemetrexed/platinum (Investigators choice of cisplatin or carboplatin). With Amendment 10 (effective date 23-Dec-2019), active participants, investigator, and sponsor personnel or delegate(s) involved in the treatment administration or clinical evaluation of the participants will be unblinded, and all participants in the 'control' arm will discontinue saline placebo. With Amendment 11 (effective date 31-Jan-2022), once the study objectives have been met or the study has ended, participants will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment. The primary hypothesis is that pembrolizumab in combination with pemetrexed/platinum chemotherapy prolongs Progression-Free Survival (PFS) and Overall Survival (OS) compared to pemetrexed/platinum chemotherapy alone.
Interventions
BIOLOGICALPembrolizumab 200 mg
IV infusion
DRUGCisplatin
IV infusion
DRUGCarboplatin
IV infusion
DRUGPemetrexed
IV infusion
DIETARY_SUPPLEMENTFolic acid 350-1000 μg
Orally; at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed.
DIETARY_SUPPLEMENTVitamin B12 1000 μg
Intramuscular injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration.
For prophylaxis; orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.
DRUGSaline solution
IV infusion
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 histologically-confirmed or cytologically confirmed diagnosis of stage IV nonsquamous NSCLC. * Has confirmation that epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-directed therapy is not indicated. * Has measurable disease. * Has not received prior systemic treatment for their advanced/metastatic NSCLC. * Can provide tumor tissue. * 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 adequate contraception for the course of the study through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents. * If male with a female partner(s) of child-bearing potential, must agree to use adequate contraception starting with the first dose of study medication through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.
Exclusion criteria
* Has predominantly squamous cell 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 medication: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease, b) Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib, cetuximab), c) Had major surgery (\<3 weeks prior to first dose) * Received radiation therapy to the lung that is \>30 Gray (Gy) within 6 months of the first dose of study medication. * Completed palliative radiotherapy within 7 days of the first dose of study medication. * Is expected to require any other form of antineoplastic therapy while on study. * Received a live-virus vaccination within 30 days of planned start of study medication. * Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, peritoneal carcinomatosis. * Known history of prior malignancy except if participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy, except for successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers. * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. * Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb). * Known sensitivity to any component of cisplatin, carboplatin or pemetrexed. * Has active autoimmune disease that has required systemic treatment in past 2 years. * Is on chronic systemic steroids. * Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam). * Is unable or unwilling to take folic acid or vitamin B12 supplementation. * Had prior treatment with any other anti-programmed cell death-1 (PD-1), or PD-ligand 1 (PD-L1) or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms. Has participated in any other pembrolizumab study 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. * Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial. * Is a regular user (including recreational use) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol). * Has symptomatic ascites or pleural effusion. * Has interstitial lung disease or a history of pneumonitis that required oral of IV glucocorticoids to assist with management. * Is pregnant or breastfeeding, or expecting to conceive or father children prior to 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 21 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS is presented. |
| Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging | Up to approximately 21 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 RECIST 1.1, 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. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging | Up to approximately 21 months | For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥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 a CR or PR until PD or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. 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. DOR assessments were based on blinded central imaging review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented. |
| Number of Participants Who Discontinued Any Study Drug Due to an AE | Up to approximately 21 months | An AE was defined as any untoward medical occurrence in a study participant administered study drug and which does not necessarily have to have a causal relationship with this study drug. The number of participants who discontinued any randomized study drug due to an AE is presented. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 21 months (Serious AEs: Up to 90 days after last dose of study treatment; Other AEs: Up to 30 days after last dose of study treatment) | An AE was defined as any untoward medical occurrence in a study participant administered study drug and which does not necessarily have to have a causal relationship with this study drug. The number of participants who experienced an AE is presented. |
| Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging | Up to approximately 21 months | ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The percentage of participants who experienced a CR or PR is presented. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria | Up to approximately 39 months | PFS was defined as the time from randomization to the first documented immune-related progressive disease (irPD) or death due to any cause, whichever occurred first. Per irRECIST, irPD was confirmed if any of the following are observed in 2 scans performed at least 4 weeks apart: target lesion sum of diameters remains ≥20 % and at least 5 mm absolute increase compared to nadir; non-target disease resulting in initial PD is qualitatively worse; new lesion resulting in initial irPD is qualitatively worse; additional new lesion(s) since last evaluation; or additional new non-target lesion progression since last evaluation. The PFS per irRECIST 1.1 is presented. |
Participant flow
Pre-assignment details
Eighty-four participants randomized to receive Control switched over to receive pembrolizumab monotherapy. Participants receiving pembrolizumab in first course and those switching over from placebo to pembrolizumab monotherapy were eligible to receive second course of pembrolizumab monotherapy if they met certain criteria. Data from second course treatment contributed to safety data only. All primary and secondary outcome measures are based on protocol-specified cutoff (2017-11-08).
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed Participants received pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m\^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m\^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m\^2 IV Q3W until progression. (Participants who received pembrolizumab 200 mg IV Q3W for up to 2 years but experienced disease progression, were eligible to receive a second course of pembrolizumab monotherapy 200 mg IV Q3W, at the investigator's discretion, for up to 1 additional year.) | 410 |
| Control Participants received saline placebo IV PLUS pemetrexed 500 mg/m\^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m\^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m\^2 IV Q3W until progression. (Effective 23-Dec-2019, participants discontinued saline placebo. If documented disease progression had occurred, and participants receiving Control met certain criteria, they were eligible to switch over to receive pembrolizumab monotherapy Q3W for the remainder of the study.) | 206 |
| Total | 616 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 329 | 181 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Sponsor Decision | 64 | 13 |
| Overall Study | Withdrawal by Subject | 13 | 9 |
Baseline characteristics
| Characteristic | Total | Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed | Control |
|---|---|---|---|
| Age, Continuous | 63.1 Years STANDARD_DEVIATION 9.3 | 63.2 Years STANDARD_DEVIATION 9.4 | 62.8 Years STANDARD_DEVIATION 9.1 |
| Platinum Chemotherapy Carboplatin | 445 Participants | 297 Participants | 148 Participants |
| Platinum Chemotherapy Cisplatin | 171 Participants | 113 Participants | 58 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Status Not Evaluable | 38 Participants | 23 Participants | 15 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Status TPS <1% | 190 Participants | 127 Participants | 63 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Status TPS ≥1% | 388 Participants | 260 Participants | 128 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 10 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 11 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 582 Participants | 387 Participants | 195 Participants |
| Sex: Female, Male Female | 253 Participants | 156 Participants | 97 Participants |
| Sex: Female, Male Male | 363 Participants | 254 Participants | 109 Participants |
| Smoking Status Former/Current Smoker | 543 Participants | 362 Participants | 181 Participants |
| Smoking Status Never Smoker | 73 Participants | 48 Participants | 25 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 | 330 / 410 | 113 / 206 | 74 / 84 | 1 / 2 | 4 / 9 |
| other Total, other adverse events | 395 / 405 | 196 / 202 | 64 / 84 | 2 / 2 | 9 / 9 |
| serious Total, serious adverse events | 233 / 405 | 102 / 202 | 29 / 84 | 0 / 2 | 2 / 9 |
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 interim analysis were censored at the date of the last follow-up. The OS is presented.
Time frame: Up to approximately 21 months
Population: The analysis population consisted of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed | Overall Survival (OS) | NA Months |
| Control | Overall Survival (OS) | 11.3 Months |
p-value: <0.0000195% CI: [0.38, 0.64]Log Rank
Primary
Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging
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 RECIST 1.1, 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. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 is presented.
Time frame: Up to approximately 21 months
Population: The analysis population consisted of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed | Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging | 8.8 Months |
| Control | Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging | 4.9 Months |
p-value: <0.0000195% CI: [0.43, 0.64]Log Rank
Secondary
Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥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 a CR or PR until PD or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. 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. DOR assessments were based on blinded central imaging review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented.
Time frame: Up to approximately 21 months
Population: The analysis population consisted of all randomized participants who experienced a confirmed CR or confirmed PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed | Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging | 11.2 Months |
| Control | Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging | 7.8 Months |
Secondary
Number of Participants Who Discontinued Any Study Drug Due to an AE
An AE was defined as any untoward medical occurrence in a study participant administered study drug and which does not necessarily have to have a causal relationship with this study drug. The number of participants who discontinued any randomized study drug due to an AE is presented.
Time frame: Up to approximately 21 months
Population: The analysis population consisted of all randomized participants who received ≥1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed | Number of Participants Who Discontinued Any Study Drug Due to an AE | 112 Participants |
| Control | Number of Participants Who Discontinued Any Study Drug Due to an AE | 30 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a study participant administered study drug and which does not necessarily have to have a causal relationship with this study drug. The number of participants who experienced an AE is presented.
Time frame: Up to approximately 21 months (Serious AEs: Up to 90 days after last dose of study treatment; Other AEs: Up to 30 days after last dose of study treatment)
Population: The analysis population consisted of all randomized participants who received ≥1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed | Number of Participants Who Experienced an Adverse Event (AE) | 404 Participants |
| Control | Number of Participants Who Experienced an Adverse Event (AE) | 200 Participants |
Secondary
Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging
ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The percentage of participants who experienced a CR or PR is presented.
Time frame: Up to approximately 21 months
Population: The analysis population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed | Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging | 47.6 Percentage of Participants |
| Control | Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging | 18.9 Percentage of Participants |
p-value: <0.000195% CI: [21.1, 35.4]Stratified Miettinen and Nurminen
Other Pre-specified
Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria
PFS was defined as the time from randomization to the first documented immune-related progressive disease (irPD) or death due to any cause, whichever occurred first. Per irRECIST, irPD was confirmed if any of the following are observed in 2 scans performed at least 4 weeks apart: target lesion sum of diameters remains ≥20 % and at least 5 mm absolute increase compared to nadir; non-target disease resulting in initial PD is qualitatively worse; new lesion resulting in initial irPD is qualitatively worse; additional new lesion(s) since last evaluation; or additional new non-target lesion progression since last evaluation. The PFS per irRECIST 1.1 is presented.
Time frame: Up to approximately 39 months
Population: The analysis population consisted of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Pemetrexed+Platinum Chemotherapy Followed by Pembrolizumab+Pemetrexed | Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria | 10.3 Months |
| Control | Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria | 5.0 Months |
p-value: <0.0000195% CI: [0.41, 0.59]Log Rank