Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized, Phase II Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Patients With Advanced Melanoma (KEYNOTE 002)

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Dacarbazine
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab 2 mg/kg<br>Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (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) | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Pembrolizumab 10 mg/kg<br>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) | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Active Comparator: Investigator-Choice Chemotherapy (ICC)<br>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) | Drug: Carboplatin<br>* Carboplatin per institutional standard<br>* Other names: PARAPLATIN®;Drug: Paclitaxel<br>* Paclitaxel per institutional standard<br>* Other names: TAXOL®;Drug: Dacarbazine<br>* Dacarbazine per institutional standard<br>* Other names: DTIC;Drug: Temozolomide<br>* Temozolomide per institutional standard<br>* Other names: TEMODAR®;|
| Experimental: ICC→Pembrolizumab 2 mg/kg<br>Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received 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 PD, toxicity, or choice. (Up to  66 months) | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* Carboplatin per institutional standard<br>* Other names: PARAPLATIN®;Drug: Paclitaxel<br>* Paclitaxel per institutional standard<br>* Other names: TAXOL®;Drug: Dacarbazine<br>* Dacarbazine per institutional standard<br>* Other names: DTIC;Drug: Temozolomide<br>* Temozolomide per institutional standard<br>* Other names: TEMODAR®;|
| Experimental: ICC→Pembrolizumab 10 mg/kg<br>Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received 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 PD, toxicity, or choice. (Up to  66 months) | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* Carboplatin per institutional standard<br>* Other names: PARAPLATIN®;Drug: Paclitaxel<br>* Paclitaxel per institutional standard<br>* Other names: TAXOL®;Drug: Dacarbazine<br>* Dacarbazine per institutional standard<br>* Other names: DTIC;Drug: Temozolomide<br>* Temozolomide per institutional standard<br>* Other names: TEMODAR®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | 
| 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. | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | 
| 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. | Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) | 
| 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. | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | 
| 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. | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | 
| 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. | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | 
| 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. | Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) | 
| 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. | Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) | 
| 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. | Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)