Non-Small Cell Lung Carcinoma
Conditions
Keywords
Programmed cell death-1 (PD-1), Programmed cell death 1 (PD1), Programmed death-ligand 1 (PDL1), PD-L1
Brief summary
This is a study to assess the efficacy and safety of pembrolizumab (MK-3475/SCH 900475) compared to standard of care (SOC) platinum-based chemotherapies in the treatment of participants with previously untreated stage IV, programmed cell death ligand 1 (PD-L1) strong expressing Non-Small Cell Lung Cancer (NSCLC). The primary hypothesis of this study is that participants with PD-L1 strong NSCLC will have a longer Progression Free Survival (PFS), as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) when treated with pembrolizumab than when treated with SOC platinum-based chemotherapies. With Amendment 09 (20 December 2017), once participants have achieved the study objective or the study has ended, participants will be discontinued from this study and enrolled in an extension study to continue protocol-defined assessments and treatment.
Detailed description
Treatment Phase: Participants randomized to pembrolizumab will be treated for up to 35 cycles or until documented progressive disease (PD) occurs. Participants randomized to SOC chemotherapies will be treated with their randomized study drug for up to 4-6 cycles. After this, participants with non-squamous histologies may choose to be treated with maintenance pemetrexed for the remainder of the study or until disease progression, unacceptable adverse event(s) (AEs), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the participant, noncompliance with study treatment or procedures requirements, the participant receives 35 treatments of study treatment (pembrolizumab arm only), or administrative reasons. Participants receiving pembrolizumab who stop drug administration after receiving 35 study treatments for reasons other than disease progression or intolerability, or participants who attain a complete response and stop study treatment may be eligible for retreatment with pembrolizumab upon experiencing disease progression. The decision to retreat with a second course of pembrolizumab will be at the discretion of the Investigator only if participants meet the criteria for retreatment and the study is ongoing. Retreatment (second course) is limited to 17 cycles. Participants randomized to receive SOC chemotherapy may be eligible to receive pembrolizumab if criteria to switch are met. Switch-Over Phase: This is only applicable for participants randomized to receive SOC. Eligible participants will be treated with pembrolizumab for the remainder of the study or until disease progression, unacceptable AEs, intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the participant, noncompliance with study treatment or procedures requirements, the participant receives 35 treatments of study treatment (pembrolizumab arm only), or administrative reasons.
Interventions
DRUGPembrolizumab
Pembrolizumab IV solution
DRUGPaclitaxel
Paclitaxel IV solution
DRUGCarboplatin
Carboplatin IV solution
DRUGPemetrexed
Pemetrexed Lyophilized Powder for Infusion
DRUGCisplatin
Cisplatin IV solution
DRUGGemcitabine
Gemcitabine Lyophilized Powder for Infusion
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
* Histological or cytological diagnosis of Stage IV NSCLC lacking epidermal growth factor receptor (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK) translocation, and received no prior systemic chemotherapy treatment for their metastatic NSCLC * At least one radiographically measurable lesion per RECIST 1.1 * Life expectancy of at least 3 months * Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status * Adequate organ function * No history of prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cervical cancer, or has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy * Provided newly obtained formalin fixed tumor tissue from a biopsy of a tumor at the time of or AFTER the diagnosis of metastatic disease has been made AND from a site not previously irradiated * PD-L1 strong expressing tumor as determined by immunohistochemistry (IHC) at a central laboratory * Female participants must have a negative pregnancy test at screening if of childbearing potential or be of non-childbearing potential * Female participants of childbearing potential and male partners with female partners of childbearing potential must agree to use 2 adequate barrier methods of contraception during the study and for 120 days after last dose of study drug and up to 180 days after last dose of chemotherapy
Exclusion criteria
* EGFR sensitizing mutation and/or ALK translocation * Has received systemic therapy for the treatment of their stage IV NSCLC. Completion of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic disease. * Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of first dose of study drug * Tumor specimen is not evaluable for PD-L1 expression by the central laboratory * Receiving systemic steroid therapy \< 3 days prior to first dose of study drug or receiving any other form of immunosuppressive medication * Expected to require any other form of systemic or localized antineoplastic therapy during the study * Received prior systemic cytotoxic chemotherapy, biological therapy, major surgery within 3 weeks of first dose of study drug; received thoracic radiation therapy of \> 30 gray (Gy) within 6 months of first dose of study drug * Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-PD-L1, anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor \[TNFR\] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) * Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis * Active autoimmune disease that has required systemic treatment in past 2 years * Allogenic tissue/solid organ transplant * Interstitial lung disease or pneumonitis that has required oral or IV steroids * Received or will receive a live vaccine within 30 days prior to first dose of study drug * Active infection requiring IV systemic therapy * Known history of human immunodeficiency virus (HIV) * Known active tuberculosis, or hepatitis B or C * Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study * Is, at the time of signing informed consent, a regular user (including recreational use) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol) * Pregnant or breastfeeding, or expecting to conceive or father children during the study and through 120 days after last dose of pembrolizumab or 180 days after last dose of SOC chemotherapy * Immediate family member who is investigational site or sponsor staff directly involved with this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Rate at Month 6 | Month 6 | PFS was defined as the time from randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or death due to any cause, whichever occurred first and was based on blinded independent central radiologists' (BICR) review. Progressive Disease (PD) was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. (Note: the appearance of one or more new lesions was also considered progression). Participants were evaluated every 9 weeks with radiographic imaging to assess their response to treatment. The data cutoff was 09-May-2016. The PFS rate at Month 6 was calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Rate | 12 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 data cutoff was 10-July-2017. The median OS rate at 12 months is presented. |
| Objective Response Rate (ORR) | Up to ~1.6 years | ORR was defined as the percentage of participants in the analysis population who experienced 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) and was assessed using RECIST 1.1 based on BICR evaluation. ORR was assessed from enrollment/treatment initiation of a participant through data cutoff of 09-May-2016. The ORR is presented for each treatment group. |
Participant flow
Pre-assignment details
Per protocol, it was planned that participants would be randomized 1:1 to receive either pembrolizumab or investigator-choice standard of care (SOC) chemotherapy and data analysis would be conducted on the two treatment arms: Pembrolizumab and SOC Chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Participants received pembrolizumab 200 mg, administered as IV infusion on Day 1 of each 21-day cycle for up to 35 cycles or until documented PD or participant discontinuation. | 154 |
| SOC Chemotherapy Participants received 1 of 5 possible standard chemotherapy regimens at the investigator's discretion by IV infusion: paclitaxel 200 mg/m\^2 and carboplatin Area Under the Curve (AUC) 5 or 6, administered on Day 1 of each 21-day cycle for 4-6 cycles; pemetrexed 500 mg/m\^2 and carboplatin AUC 5 or 6, on Day 1 of each 21-day cycle for 4-6 cycles; pemetrexed 500 mg/m\^2 and cisplatin 75 mg/m\^2, on Day 1 of each 21-day cycle for 4-6 cycles; gemcitabine 1250 mg/m\^2, administered on Days 1 and 8 of each 21-day cycle and carboplatin AUC 5 or 6, on Day 1 of a 21-day cycle, for 4-6 cycles; gemcitabine 1250 mg/m\^2, on Days 1 and 8 of each 21-day cycle and cisplatin 75 mg/m\^2, on Day 1 of each 21-day cycle for 4-6 cycles or until documented PD or participant discontinuation. Participants with documented disease progression following chemotherapy can switch to receive pembrolizumab for up to 35 cycles (approximately 2 years). Eligible participants who switched to and then 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 (approximately 1 additional year). | 151 |
| Total | 305 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 9 |
| Overall Study | Death | 92 | 112 |
| Overall Study | Follow up ended by sponsor | 43 | 20 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Withdrawal by Subject | 6 | 7 |
Baseline characteristics
| Characteristic | Pembrolizumab | SOC Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 63.9 Years STANDARD_DEVIATION 10.1 | 64.6 Years STANDARD_DEVIATION 9.5 | 64.2 Years STANDARD_DEVIATION 9.8 |
| Eastern Cooperative Oncology Group (ECOG) Status (0, 1 or 2) ECOG = 0 | 54 Rating | 53 Rating | 107 Rating |
| Eastern Cooperative Oncology Group (ECOG) Status (0, 1 or 2) ECOG = 1 | 99 Rating | 98 Rating | 197 Rating |
| Eastern Cooperative Oncology Group (ECOG) Status (0, 1 or 2) ECOG = 2 | 1 Rating | 0 Rating | 1 Rating |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 148 Participants | 135 Participants | 283 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 11 Participants | 16 Participants |
| Geographic Region of Enrolling Site East Asia | 21 Participants | 19 Participants | 40 Participants |
| Geographic Region of Enrolling Site Non-East Asia | 133 Participants | 132 Participants | 265 Participants |
| Histology ADENOCARCINOMA | 104 Participants | 108 Participants | 212 Participants |
| Histology ADENOSQUAMOUS | 2 Participants | 2 Participants | 4 Participants |
| Histology LARGE CELL CARCINOMA | 2 Participants | 2 Participants | 4 Participants |
| Histology NON-SQUAMOUS CELL CARCINOMA | 5 Participants | 7 Participants | 12 Participants |
| Histology POORLY DIFFERENTIATED | 9 Participants | 3 Participants | 12 Participants |
| Histology POORLY DIFFERENTIATED SQUAMOUS CELL CARCINOMA | 0 Participants | 1 Participants | 1 Participants |
| Histology SARCOMATOID | 3 Participants | 2 Participants | 5 Participants |
| Histology SQUAMOUS CELL CARCINOMA | 29 Participants | 26 Participants | 55 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 21 Participants | 46 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 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 | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 125 Participants | 126 Participants | 251 Participants |
| Sex: Female, Male Female | 62 Participants | 56 Participants | 118 Participants |
| Sex: Female, Male Male | 92 Participants | 95 Participants | 187 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 | 103 / 154 | 60 / 151 | 62 / 83 | 4 / 12 | 1 / 1 |
| other Total, other adverse events | 140 / 154 | 142 / 150 | 72 / 83 | 10 / 12 | 0 / 1 |
| serious Total, serious adverse events | 79 / 154 | 70 / 150 | 27 / 83 | 2 / 12 | 0 / 1 |
Outcome results
Primary
Progression Free Survival (PFS) Rate at Month 6
PFS was defined as the time from randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or death due to any cause, whichever occurred first and was based on blinded independent central radiologists' (BICR) review. Progressive Disease (PD) was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. (Note: the appearance of one or more new lesions was also considered progression). Participants were evaluated every 9 weeks with radiographic imaging to assess their response to treatment. The data cutoff was 09-May-2016. The PFS rate at Month 6 was calculated.
Time frame: Month 6
Population: The Intention-to-treat (ITT) population included all randomized participants. Participants were included in the treatment group to which they were randomized, regardless of whether or not they received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Progression Free Survival (PFS) Rate at Month 6 | 62.1 Percentage of Participants |
| SOC Chemotherapy | Progression Free Survival (PFS) Rate at Month 6 | 50.3 Percentage of Participants |
p-value: <0.00195% CI: [0.37, 0.68]Regression, Cox
Secondary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants in the analysis population who experienced 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) and was assessed using RECIST 1.1 based on BICR evaluation. ORR was assessed from enrollment/treatment initiation of a participant through data cutoff of 09-May-2016. The ORR is presented for each treatment group.
Time frame: Up to ~1.6 years
Population: The ITT population included all randomized participants. Participants were included in the treatment group to which they were randomized, regardless of whether or not they received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Objective Response Rate (ORR) | 44.8 Percentage of Participants |
| SOC Chemotherapy | Objective Response Rate (ORR) | 27.8 Percentage of Participants |
Comparison: H0: difference in %=0 vs. H1: difference in % \>0p-value: 0.001195% CI: [6, 27]Miettinen & Nurminem method
Secondary
Overall Survival (OS) Rate
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 data cutoff was 10-July-2017. The median OS rate at 12 months is presented.
Time frame: 12 months
Population: The ITT population included all randomized participants. Participants were included in the treatment group to which they were randomized, regardless of whether or not they received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Overall Survival (OS) Rate | 70.3 Percentage of Participants |
| SOC Chemotherapy | Overall Survival (OS) Rate | 54.8 Percentage of Participants |
p-value: 0.00295% CI: [0.47, 0.86]Regression, Cox