Malignant Melanoma
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
Brief summary
This study was conducted to compare survival using pembrolizumab (SCH 900475, MK-3475) or standard chemotherapy in participants with advanced melanoma (MEL) who had progressed after prior therapy. Initial Treatment Period: Participants were initially randomized to receive either low-dose (2 mg/kg) pembrolizumab, higher dose (10 mg/kg) pembrolizumab or Investigator-choice chemotherapy (ICC). The four standard chemotherapy choices were: carboplatin + paclitaxel, paclitaxel alone, dacarbazine, or temozolomide. The randomization to either pembrolizumab or ICC was conducted in an open-label fashion. The starting pembrolizumab dose was initially blinded to Investigators and participants until Amendment 03. With Amendment 03, all ongoing pembrolizumab participants were to be treated with open label, fixed dose pembrolizumab 200 mg, instead of a weight-based dosing of pembrolizumab. Switch-to-Pembrolizumab Treatment Period: Participants who were initially randomized to receive ICC and experienced progressive disease (PD) may have been eligible to switch to receiving pembrolizumab provided they met protocol-specified requirements for switching. Qualified participants were re-randomized to receive either pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg in a double-blind fashion. Participants who qualified to switch to pembrolizumab must have completed a washout period of ≥28 days from last dose of chemotherapy before receiving pembrolizumab. With Amendment 03, all switched-to-pembrolizumab participants were to be treated with open-label, fixed dose pembrolizumab 200 mg instead of a weight-based dosing of pembrolizumab.
Detailed description
Two interim and one final statistical analyses were planned for and conducted during this study: * Interim Analysis 1 (futility analysis), * Interim Analysis 2 (\ 18 months into study): database cutoff date 12-May-2014, and * Final Analysis (\ 36 months into study): database cutoff date 16-Nov-2015. The End of Trial Analysis for the study was conducted at \ 75 months into the study: database cutoff date 31-Jan-2019.
Interventions
BIOLOGICALPembrolizumab
IV infusion
DRUGCarboplatin
Carboplatin per institutional standard
DRUGPaclitaxel
Paclitaxel per institutional standard
DRUGDacarbazine
Dacarbazine per institutional standard
DRUGTemozolomide
Temozolomide per institutional standard
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic MEL not amenable to local therapy * Participants must be refractory to ipilimumab * Participants with BRAF gene mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor * Must consent to allow correlative studies; must provide a newly obtained tissue/biopsy specimen (or specimen obtained within 60 days of consenting) * Radiographically measurable disease * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Exclusion criteria
* Chemotherapy, radiation therapy, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from the AEs due to cancer therapies administered more than 4 weeks earlier * Disease progression within 24 weeks of last dose of ipilimumab * 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 * Chronic systemic steroid therapy within 2 weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication * Known history of any other than the current malignancy excepting adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, breast cancer, or other in situ cancers * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Active autoimmune disease or a history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents * Prior treatment with any other anti-programmed cell death (PD) agent * Active infection requiring systemic therapy * Known history of Human Immunodeficiency Virus (HIV) * Active Hepatitis B or Hepatitis C * 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 through 120 days after last dose of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) - Initial Treatment Period | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | 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 at least a 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 have also demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Analysis of PFS was based on an integrated radiology and oncology (IRO) assessment and was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS. |
| Interim Overall Survival (OS) - Initial Treatment Period | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS. |
| Final Overall Survival (OS) - Initial Treatment Period | Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) | OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | The BOR was assessed using RECIST 1.1 and was recorded from the start of the second line of study drug (pembrolizumab) until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For the switch-to-pembrolizumab treatment groups, BOR was based on independent review committee (IRC) assessment. The BOR for switched-to pembrolizumab treatment groups is presented. |
| Duration of Response (DOR) - Initial Treatment Period | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | For participants who demonstrated a confirmed response (Complete Response \[CR\]: disappearance of all target lesions or Partial Response \[PR\]: ≥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 CR or PR until disease progression 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. DOR analysis was based on IRO assessment. Analysis of DOR was not planned or analyzed for the switch-to-pembrolizumab treatment groups. Median DOR for participants who demonstrated a confirmed response is presented. |
| Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period | Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) | OS was defined as the time from randomization to death due to any cause. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented. |
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study | Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented. |
| Number of Participants Who Experienced an Adverse Event (AE) - Overall Study | Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study drug, was also an AE. Participants were included in the treatment group in which an AE was experienced. The number of participants who experienced at least one AE is presented. |
| Overall Response Rate (ORR) - Initial Treatment Period | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | 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 using RECIST 1.1. Analysis of ORR was not planned or conducted for the switch-to-pembrolizumab treatment groups. The percentage of participants who experienced a CR or PR is presented. This was the final analysis for ORR. |
| Best Overall Response (BOR) - Initial Treatment Period | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | BOR was assessed by independent radiology review using RECIST 1.1 and was recorded from randomization until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. BOR for the Initial Treatment Period was based on IRO. BOR for participants during the Initial Treatment Period is presented. |
Participant flow
Pre-assignment details
This end of trial analysis is based on a trial closure database cutoff date of 31-Jan-2019.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab 2 mg/kg Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to \
66 months) | 180 |
| Pembrolizumab 10 mg/kg Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to \
66 months) | 181 |
| Investigator-Choice Chemotherapy (ICC) Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to \
66 months) | 179 |
| Total | 540 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Initial Treatment Period | Death | 139 | 129 | 71 | 0 | 0 |
| Initial Treatment Period | Lost to Follow-up | 5 | 3 | 0 | 0 | 0 |
| Initial Treatment Period | Switched to Pembrolizumab | 0 | 0 | 98 | 0 | 0 |
| Initial Treatment Period | Withdrawal by Subject | 3 | 2 | 4 | 0 | 0 |
| Switch to Pembrolizumab Treatment Period | Death | 0 | 0 | 0 | 35 | 37 |
| Switch to Pembrolizumab Treatment Period | Lost to Follow-up | 0 | 0 | 0 | 2 | 1 |
| Switch to Pembrolizumab Treatment Period | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Pembrolizumab 2 mg/kg | Pembrolizumab 10 mg/kg | Investigator-Choice Chemotherapy (ICC) | Total |
|---|---|---|---|---|
| Age, Continuous | 59.5 Years STANDARD_DEVIATION 14.9 | 60.1 Years STANDARD_DEVIATION 13.3 | 60.5 Years STANDARD_DEVIATION 12.7 | 60.1 Years STANDARD_DEVIATION 13.6 |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status PD-L1 Negative | 48 Participants | 46 Participants | 40 Participants | 134 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status PD-L1 Positive | 99 Participants | 97 Participants | 98 Participants | 294 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status Unknown | 33 Participants | 38 Participants | 41 Participants | 112 Participants |
| Sex: Female, Male Female | 76 Participants | 72 Participants | 65 Participants | 213 Participants |
| Sex: Female, Male Male | 104 Participants | 109 Participants | 114 Participants | 327 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 | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 71 / 73 | 0 / 53 | 0 / 45 | 139 / 178 | 129 / 179 | 35 / 53 | 37 / 45 |
| other Total, other adverse events | 66 / 73 | 52 / 53 | 44 / 45 | 158 / 178 | 176 / 179 | 48 / 53 | 36 / 45 |
| serious Total, serious adverse events | 33 / 73 | 15 / 53 | 9 / 45 | 91 / 178 | 78 / 179 | 18 / 53 | 18 / 45 |
Outcome results
Primary
Final Overall Survival (OS) - Initial Treatment Period
OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS.
Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Population: The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab 2 mg/kg | Final Overall Survival (OS) - Initial Treatment Period | 13.4 Months |
| Pembrolizumab 10 mg/kg | Final Overall Survival (OS) - Initial Treatment Period | 14.7 Months |
| Investigator-Choice Chemotherapy (ICC) | Final Overall Survival (OS) - Initial Treatment Period | 11.0 Months |
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.114695% CI: [0.68, 1.1]Log Rank
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.002395% CI: [0.55, 0.9]Log Rank
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.14995% CI: [0.66, 1.07]Log Rank
Primary
Interim Overall Survival (OS) - Initial Treatment Period
OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS.
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Population: The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab 2 mg/kg | Interim Overall Survival (OS) - Initial Treatment Period | 13.4 Months |
| Pembrolizumab 10 mg/kg | Interim Overall Survival (OS) - Initial Treatment Period | 14.7 Months |
| Investigator-Choice Chemotherapy (ICC) | Interim Overall Survival (OS) - Initial Treatment Period | 11.0 Months |
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.117395% CI: [0.67, 1.1]Log Rank
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.010695% CI: [0.57, 0.96]Log Rank
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.290595% CI: [0.67, 1.12]Log Rank
Primary
Progression-free Survival (PFS) - Initial Treatment Period
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 at least a 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 have also demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Analysis of PFS was based on an integrated radiology and oncology (IRO) assessment and was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS.
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Population: The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab 2 mg/kg | Progression-free Survival (PFS) - Initial Treatment Period | 2.9 Months |
| Pembrolizumab 10 mg/kg | Progression-free Survival (PFS) - Initial Treatment Period | 3.0 Months |
| Investigator-Choice Chemotherapy (ICC) | Progression-free Survival (PFS) - Initial Treatment Period | 2.8 Months |
p-value: <0.000195% CI: [0.46, 0.73]Log Rank
p-value: <0.000195% CI: [0.37, 0.6]Log Rank
p-value: 0.124795% CI: [0.66, 1.05]Log Rank
Secondary
Best Overall Response (BOR) - Initial Treatment Period
BOR was assessed by independent radiology review using RECIST 1.1 and was recorded from randomization until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. BOR for the Initial Treatment Period was based on IRO. BOR for participants during the Initial Treatment Period is presented.
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Population: The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Progressive Disease | 46.7 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Not Evaluable | 13.3 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | No Assessment | 0.6 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Partial Response | 18.9 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | No Disease | 0.6 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Stable Disease | 16.7 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Complete Response | 3.3 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Progressive Disease | 47.5 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Complete Response | 7.2 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Partial Response | 20.4 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Not Evaluable | 9.9 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | Stable Disease | 14.9 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | No Assessment | 0.0 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Initial Treatment Period | No Disease | 0.0 Percentage of Participants |
| Investigator-Choice Chemotherapy (ICC) | Best Overall Response (BOR) - Initial Treatment Period | No Assessment | 0.0 Percentage of Participants |
| Investigator-Choice Chemotherapy (ICC) | Best Overall Response (BOR) - Initial Treatment Period | No Disease | 0.0 Percentage of Participants |
| Investigator-Choice Chemotherapy (ICC) | Best Overall Response (BOR) - Initial Treatment Period | Complete Response | 0.0 Percentage of Participants |
| Investigator-Choice Chemotherapy (ICC) | Best Overall Response (BOR) - Initial Treatment Period | Partial Response | 4.5 Percentage of Participants |
| Investigator-Choice Chemotherapy (ICC) | Best Overall Response (BOR) - Initial Treatment Period | Stable Disease | 19.0 Percentage of Participants |
| Investigator-Choice Chemotherapy (ICC) | Best Overall Response (BOR) - Initial Treatment Period | Progressive Disease | 61.5 Percentage of Participants |
| Investigator-Choice Chemotherapy (ICC) | Best Overall Response (BOR) - Initial Treatment Period | Not Evaluable | 15.1 Percentage of Participants |
Secondary
Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period
The BOR was assessed using RECIST 1.1 and was recorded from the start of the second line of study drug (pembrolizumab) until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For the switch-to-pembrolizumab treatment groups, BOR was based on independent review committee (IRC) assessment. The BOR for switched-to pembrolizumab treatment groups is presented.
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Population: The analysis population consisted of all randomized participants in ICC who switched to receiving pembrolizumab. Participants were included in the treatment group to which they were re-randomized (switched) for this efficacy analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Not Evaluable | 11.3 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Complete Response | 1.9 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Progressive Disease | 54.7 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Partial Response | 17.0 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | No Assessment | 0.0 Percentage of Participants |
| Pembrolizumab 2 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Stable Disease | 15.1 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | No Assessment | 2.2 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Progressive Disease | 55.6 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Not Evaluable | 13.3 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Stable Disease | 11.1 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Complete Response | 4.4 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period | Partial Response | 13.3 Percentage of Participants |
Secondary
Duration of Response (DOR) - Initial Treatment Period
For participants who demonstrated a confirmed response (Complete Response \[CR\]: disappearance of all target lesions or Partial Response \[PR\]: ≥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 CR or PR until disease progression 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. DOR analysis was based on IRO assessment. Analysis of DOR was not planned or analyzed for the switch-to-pembrolizumab treatment groups. Median DOR for participants who demonstrated a confirmed response is presented.
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Population: The analysis population consisted of all randomized participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab 2 mg/kg | Duration of Response (DOR) - Initial Treatment Period | 22.8 Months |
| Pembrolizumab 10 mg/kg | Duration of Response (DOR) - Initial Treatment Period | NA Months |
| Investigator-Choice Chemotherapy (ICC) | Duration of Response (DOR) - Initial Treatment Period | 6.8 Months |
Secondary
Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period
OS was defined as the time from randomization to death due to any cause. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented.
Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Population: The analysis population consisted of all randomized participants who had a PD-L1 tumor expression status assessment. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pembrolizumab 2 mg/kg | Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period | PD-L1 Positive | 15.0 Months |
| Pembrolizumab 2 mg/kg | Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period | PD-L1 Negative | 10.5 Months |
| Pembrolizumab 10 mg/kg | Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period | PD-L1 Positive | 17.5 Months |
| Pembrolizumab 10 mg/kg | Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period | PD-L1 Negative | 13.4 Months |
| Investigator-Choice Chemotherapy (ICC) | Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period | PD-L1 Positive | 12.1 Months |
| Investigator-Choice Chemotherapy (ICC) | Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period | PD-L1 Negative | 9.3 Months |
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.311395% CI: [0.66, 1.28]Log Rank
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.020895% CI: [0.5, 0.99]Log Rank
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.049695% CI: [0.5, 1]Log Rank
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.604395% CI: [0.65, 1.76]Log Rank
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.033595% CI: [0.37, 1.04]Log Rank
Comparison: Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels \[≥110% ULN\]); \& BRAF mutational status (mutant vs. wild-type)p-value: 0.150495% CI: [0.44, 1.13]Log Rank
Secondary
Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented.
Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Population: The analysis population consisted of all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab 2 mg/kg | Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study | 29 Participants |
| Pembrolizumab 10 mg/kg | Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study | 33 Participants |
| Investigator-Choice Chemotherapy (ICC) | Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study | 13 Participants |
| ICC→Pembrolizumab 2 mg/kg | Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study | 1 Participants |
| ICC→Pembrolizumab 10 mg/kg | Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study | 1 Participants |
| ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) | Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study | 4 Participants |
| ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab) | Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study | 4 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE) - Overall Study
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study drug, was also an AE. Participants were included in the treatment group in which an AE was experienced. The number of participants who experienced at least one AE is presented.
Time frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Population: The analysis population consisted of all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab 2 mg/kg | Number of Participants Who Experienced an Adverse Event (AE) - Overall Study | 172 Participants |
| Pembrolizumab 10 mg/kg | Number of Participants Who Experienced an Adverse Event (AE) - Overall Study | 179 Participants |
| Investigator-Choice Chemotherapy (ICC) | Number of Participants Who Experienced an Adverse Event (AE) - Overall Study | 71 Participants |
| ICC→Pembrolizumab 2 mg/kg | Number of Participants Who Experienced an Adverse Event (AE) - Overall Study | 52 Participants |
| ICC→Pembrolizumab 10 mg/kg | Number of Participants Who Experienced an Adverse Event (AE) - Overall Study | 45 Participants |
| ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) | Number of Participants Who Experienced an Adverse Event (AE) - Overall Study | 53 Participants |
| ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab) | Number of Participants Who Experienced an Adverse Event (AE) - Overall Study | 41 Participants |
Secondary
Overall Response Rate (ORR) - Initial Treatment Period
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 using RECIST 1.1. Analysis of ORR was not planned or conducted for the switch-to-pembrolizumab treatment groups. The percentage of participants who experienced a CR or PR is presented. This was the final analysis for ORR.
Time frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
Population: The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab 2 mg/kg | Overall Response Rate (ORR) - Initial Treatment Period | 22.2 Percentage of Participants |
| Pembrolizumab 10 mg/kg | Overall Response Rate (ORR) - Initial Treatment Period | 27.6 Percentage of Participants |
| Investigator-Choice Chemotherapy (ICC) | Overall Response Rate (ORR) - Initial Treatment Period | 4.5 Percentage of Participants |