Melanoma
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
Brief summary
This study will evaluate the safety and efficacy of 2 different dosing schedules of pembrolizumab (MK-3475), every 2 weeks (Q2W) and every 3 weeks (Q3W), and compare the 2 schedules to treatment with ipilimumab in ipilimumab-naïve participants with unresectable or metastatic melanoma. The primary hypotheses are that pembrolizumab is superior to ipilimumab with respect to progression-free survival (PFS) and overall survival (OS).
Detailed description
Participants assigned to a primary course of pembrolizumab can receive up to 24 months of treatment. Participants with Stable Disease (SD) or better will then proceed to Post Treatment Follow-up. All efficacy and safety analyses will be based on the primary pembrolizumab course. Participants who experience disease progression during the Post Treatment Follow-up will be eligible for a Second Course of pembrolizumab treatment for up to 1 additional year. With Amendment 05, all Second Course participants will be treated with a fixed dose of pembrolizumab 200 mg Q3W. With Amendment 06, after the study has achieved its key objectives 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.
Interventions
BIOLOGICALPembrolizumab
10 mg/kg IV, administered Q2W or Q3W based upon randomization.
BIOLOGICALIpilimumab
3 mg/kg IV Q3W.
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
* Histologically-confirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable to local therapy (excluding uveal or ocular melanoma) * At least one measurable lesion * No prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (first line) or one prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (second line) * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Archived tissue sample or new biopsy sample * Female participants of childbearing potential must agree to use effective contraception from Visit 1 to 120 days after the last dose of study drug; male participants must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug
Exclusion criteria
* Prior treatment with ipilimumab or other anti-cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) agent or any anti-programmed cell death (PD-1 or PD-L2) agent * Chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or not recovered from adverse events caused by cancer therapeutics administered more than four weeks earlier * Currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug * Expected to require any other form of systemic or localized antineoplastic therapy while on study * On any systemic steroid therapy within one week before the planned date for first dose of randomized treatment or on any other form of immunosuppressive medication * History of a malignancy (other than the disease under treatment in the study) within 5 years prior to first study drug administration, excluding adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers. * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases are eligible * Severe hypersensitivity reaction to treatment with another monoclonal antibody * Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents * Active infection requiring systemic therapy * Known history of Human Immunodeficiency Virus (HIV) * Known history of or positive for Hepatitis B or C * Known psychiatric or substance abuse disorder * Regular user (including recreational use) of 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 within the projected duration of the study * Received a live vaccine within 30 days prior to first dose of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Radiology Plus Oncology Review (IRO) | Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014) | PFS was defined as the time from randomization to the first documented disease progression, based on blinded Independent Radiology plus Oncology review (IRO) using RECIST 1.1, or death due to any cause, whichever occurred first. Disease progression was defined as a 20% or greater increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of new lesions. The primary analysis of PFS was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014. |
| Percentage of Participants With Overall Survival (OS) at 12 Months | Month 12 | OS was defined as the time from randomization to death due to any cause. The percentage of participants with OS (OS rate) at 12 months was reported for each arm. The reported percentage was estimated using a product-limit (Kaplan-Meier) method for censored data; data were censored at the date of cut-off. The primary analysis of OS was performed at the time of the second protocol pre-specified statistical analysis, with data cut-off of 03-Mar-2015. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO | Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014) | ORR was defined as the percentage of the participants with a best tumor response of complete response (CR: disappearance of all target lesions with any pathological lymph nodes having a reduction in short axis to \<10 mm) or partial response (PR: ≥30% decrease in the sum of diameters of target lesions), based on IRO using RECIST 1.1. The primary analysis of ORR was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014. |
Participant flow
Recruitment details
Participants with advanced melanoma were recruited to receive ipilimumab once every 3 weeks (Q3W), or a primary course of pembrolizumab administered every 2 weeks (Q2W) or every 3 weeks (Q3W).
Pre-assignment details
834 participants were randomized 1:1:1 to receive ipilimumab Q3W, pembrolizumab Q2W, or pembrolizumab Q3W. For participants receiving pembrolizumab, all safety and efficacy results data reported are for the primary pembrolizumab course received.
Participants by arm
| Arm | Count |
|---|---|
| Ipilimumab Participants received ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months). | 278 |
| Pembrolizumab Q2W Participants received pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months. | 279 |
| Pembrolizumab Q3W Participants received pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months. | 277 |
| Total | 834 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 12 | 5 | 9 |
| Overall Study | Clinical progression | 3 | 2 | 2 |
| Overall Study | Death | 153 | 154 | 147 |
| Overall Study | Lost to Follow-up | 6 | 3 | 8 |
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 32 | 14 | 12 |
Baseline characteristics
| Characteristic | Ipilimumab | Pembrolizumab Q2W | Pembrolizumab Q3W | Total |
|---|---|---|---|---|
| Age, Continuous | 59.9 Years STANDARD_DEVIATION 14.2 | 59.9 Years STANDARD_DEVIATION 14.6 | 61.2 Years STANDARD_DEVIATION 13.6 | 60.3 Years STANDARD_DEVIATION 14.1 |
| Sex: Female, Male Female | 116 Participants | 118 Participants | 103 Participants | 337 Participants |
| Sex: Female, Male Male | 162 Participants | 161 Participants | 174 Participants | 497 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 173 / 278 | 166 / 279 | 162 / 277 |
| other Total, other adverse events | 220 / 256 | 257 / 278 | 247 / 277 |
| serious Total, serious adverse events | 77 / 256 | 89 / 278 | 90 / 277 |
Outcome results
Primary
Percentage of Participants With Overall Survival (OS) at 12 Months
OS was defined as the time from randomization to death due to any cause. The percentage of participants with OS (OS rate) at 12 months was reported for each arm. The reported percentage was estimated using a product-limit (Kaplan-Meier) method for censored data; data were censored at the date of cut-off. The primary analysis of OS was performed at the time of the second protocol pre-specified statistical analysis, with data cut-off of 03-Mar-2015.
Time frame: Month 12
Population: The ITT population, comprising all participants as randomized to a study arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ipilimumab | Percentage of Participants With Overall Survival (OS) at 12 Months | 58.2 Percentage of participants |
| Pembrolizumab Q2W | Percentage of Participants With Overall Survival (OS) at 12 Months | 74.1 Percentage of participants |
| Pembrolizumab Q3W | Percentage of Participants With Overall Survival (OS) at 12 Months | 68.4 Percentage of participants |
Comparison: Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1).p-value: 0.0005295% CI: [0.47, 0.83]Regression, Cox
Comparison: Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1).p-value: 0.0035895% CI: [0.52, 0.9]Regression, Cox
Comparison: Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1).p-value: 0.5131995% CI: [0.67, 1.22]Regression, Cox
Primary
Progression-free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Radiology Plus Oncology Review (IRO)
PFS was defined as the time from randomization to the first documented disease progression, based on blinded Independent Radiology plus Oncology review (IRO) using RECIST 1.1, or death due to any cause, whichever occurred first. Disease progression was defined as a 20% or greater increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of new lesions. The primary analysis of PFS was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014.
Time frame: Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014)
Population: The ITT population, comprising all participants as randomized to a study arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab | Progression-free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Radiology Plus Oncology Review (IRO) | 2.8 Months |
| Pembrolizumab Q2W | Progression-free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Radiology Plus Oncology Review (IRO) | 5.5 Months |
| Pembrolizumab Q3W | Progression-free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Radiology Plus Oncology Review (IRO) | 4.1 Months |
Comparison: Statistical testing was stratified by line of therapy (1st vs. 2nd), programmed cell death ligand 1 (PD-L1) status (positive vs. negative) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1)p-value: <0.0000195% CI: [0.46, 0.72]Log Rank
Comparison: Statistical testing was stratified by line of therapy (1st vs. 2nd), programmed cell death ligand 1 (PD-L1) status (positive vs. negative) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1)p-value: <0.0000195% CI: [0.47, 0.72]Log Rank
Comparison: Statistical testing was stratified by line of therapy (1st vs. 2nd), programmed cell death ligand 1 (PD-L1) status (positive vs. negative) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1)p-value: 0.7586995% CI: [0.77, 1.21]Log Rank
Secondary
Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO
ORR was defined as the percentage of the participants with a best tumor response of complete response (CR: disappearance of all target lesions with any pathological lymph nodes having a reduction in short axis to \<10 mm) or partial response (PR: ≥30% decrease in the sum of diameters of target lesions), based on IRO using RECIST 1.1. The primary analysis of ORR was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014.
Time frame: Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014)
Population: The ITT population, comprising all participants as randomized to a study arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ipilimumab | Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO | 11.9 Percentage of Participants |
| Pembrolizumab Q2W | Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO | 33.7 Percentage of Participants |
| Pembrolizumab Q3W | Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO | 32.9 Percentage of Participants |
Comparison: Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1)p-value: 0.0001395% CI: [7.8, 24.5]Miettinen & Nurmimen
Comparison: Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1)p-value: 0.0000295% CI: [9.5, 25.6]Miettinen & Nurmimen
Comparison: Statistical testing was stratified by line of therapy (1st vs. 2nd), PD-L1) status (positive vs. negative) and ECOG performance status (0 vs. 1)p-value: 0.8263695% CI: [-10.6, 8.6]Miettinen & Nurmimen