Cancer, Solid Tumor
Conditions
Keywords
Melanoma, Carcinoma, Cancer, Advanced cancer, Metastatic cancer, Metastatic melanoma, Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
Brief summary
The present study has 5 parts. In Parts A and A1, the dose of intravenous (IV) pembrolizumab (MK-3475) will be escalated from 1 to 10 mg/kg to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for participants with a histologically- or cytologically-confirmed diagnosis of any type of carcinoma or melanoma (MEL) by evaluating the Dose Limiting Toxicities (DLTs). Following completion of the dose escalation, additional patients will be enrolled in Part A2 to further define pharmacokinetic characteristics. Part B of the study will investigate the safety, tolerability, and efficacy of pembrolizumab (2 mg/kg and 10 mg/kg) in participants with advanced or metastatic MEL and compare every 2 week dosing (Q2W) to every 3 week dosing (Q3W). Part C of the study will investigate the safety, tolerability, and efficacy of pembrolizumab administered at 10 mg/kg Q3W in participants with non-small cell lung carcinoma (NSCLC) that is locally advanced or metastatic. Part D of the study will investigate the low and high doses of study drug identified in Parts A and B (2 mg/kg and 10 mg/kg) administered Q3W in participants with advanced or metastatic MEL. Part E (closed with Amendment 7) was planned to investigate low, medium, and high doses of pembrolizumab in combination with standard chemotherapy in participants with locally advanced or metastatic NSCLC. Part F will investigate low and high doses of pembrolizumab (2 mg/kg and 10 mg/kg) administered Q2W or Q3W in treatment-naive and previously-treated participants with NSCLC with programmed cell death 1 ligand (PD-L1) gene expression. The primary hypotheses are the following: that pembrolizumab will have acceptable safety and tolerability; that pembrolizumab will show a clinically meaningful response rate (RR) or disease-control rate (DCR) in participants with melanoma (ipilimumab-refractory or not) and NSCLC, and that pembrolizumab will show a more clinically meaningful RR in participants with either cancer whose tumors express PD-L1.
Detailed description
Per protocol, all participants who were receiving study intervention or in survival follow-up could enroll in the extension study, KEYNOTE-587 (NCT03486873), which would allow further study participation after the Primary Completion Date cut-off. Thus, all efficacy outcome measures except for survival (Overall Survival \[OS\]) were to be followed up to the Interim Database cut-off of 18-Sept-2018, and the primary safety analyses (except for the DLT analysis) and Overall Survival were to be followed up to the study Primary Completion Date (Final Database cut-off of 05-Nov-2018). Five participants did not have end of study assessments completed by the Primary Completion Date cut-off and were subsequently followed up to the Study Completion Date (11-Dec-2018). End of treatment and end of study assessments are missing for these 5 and the status was noted as unknown as of the Primary Completion Date cut-off. Per protocol, any safety information after the Primary Completion Date cut-off (Final Database cut-off of 05-Nov-2018) would not be included in the safety analysis but reported by the Investigator to the Sponsor via the Sponsor Communication Form and filed in the electronic Trial Master File.
Interventions
BIOLOGICALPembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
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
* In Part A: Histological or cytological diagnosis of MEL or any type of carcinoma, progressive metastatic disease, or progressive locally advanced disease not amenable to local therapy. In Parts B and D of the study, histological or cytological diagnoses of metastatic MEL with progressive locally advanced or metastatic disease. In Parts C and F, histological or cytological diagnosis of NSCLC. In Part F1, participants with Stage IV NSCLC without prior systemic therapy may be eligible. * Failure of established standard medical anti-cancer therapies for a given tumor type or intolerance to such therapy. * In Parts B, C, D, or F of the study, MEL or NSCLC must be measurable by imaging. * In Part F of the study, NSCLC with PD-L1 gene expression. * Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. * Adequate organ function. * Female participants of childbearing potential should have a negative urine or serum pregnancy test prior to receiving study medication * Female participants of childbearing potential must be willing to use adequate contraception from study start, through the course of the study, and for 120 days after the last dose of study medication * Male participants of childbearing potential must agree to use adequate contraception from the first dose of study medication through 120 days after the last dose of study medication
Exclusion criteria
* Chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the first dose of study therapy, or not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the adverse events caused by therapy administered more than 4 weeks prior to first dose. * Participation in a study of an investigational agent or using an investigational device within 30 days of administration of pembrolizumab, with the exception of participants in the follow-up phase. * Other form(s) of antineoplastic therapy anticipated during the period of the study. * History of non-infectious pneumonitis requiring treatment with steroids, or has a history of interstitial lung disease. * Medical condition that requires chronic systemic steroid therapy, or on any other form of immunosuppressive medication, excepting use of inhaled steroids. * Risk factors for bowel obstruction or bowel perforation (including a history of acute diverticulitis, intra-abdominal abscess, abdominal carcinomatosis). * History of a hematologic malignancy, malignant primary brain tumor, malignant sarcoma, or another malignant primary solid tumor, unless no evidence of that disease for 5 years. * Active central nervous system (CNS) metastases and/or carcinomatous meningitis. * Previous severe hypersensitivity reaction to another monoclonal antibody (mAb). * Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents, except vitiligo or resolved childhood asthma/atopy. * Prior therapy with another anti-programmed cell death (PD)-1 agent or previously enrolled in any pembrolizumab trial. * Active infection requiring therapy. * Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface Antigen \[HBsAg\] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid \[HCV RNA\] (qualitative) is detected). * Regular use of illicit drugs or a recent history (within the last year) of substance abuse (including alcohol). * Symptomatic ascites or pleural effusion. * Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) in Participants With Solid Tumors (Parts A and A1) | Up to 28 days in Cycle 1 | DLTs were assessed according to NCI-CTCAE v.4.0 during the first cycle (28 days) and were defined as occurrence of any of the following toxicities if judged by the investigator to be possibly, probably or definitely related to study drug administration: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥14 days; Gr 3 nonhematologic toxicity lasting \>3 days despite optimal supportive care; any Grade 3 non-hematologic laboratory value if medical intervention was required to treat the participant, the abnormality led to hospitalization, or the abnormality persisted for \>1 week; Gr 3 or 4 febrile neutropenia; thrombocytopenia \<25,000 cells/mm\^3 (if associated with a bleeding event requiring an elective platelet transfusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to an Intensive Care Unit); or Gr 5 toxicity. The number of participants in Part A and Part A1 with a DLT were reported by pembrolizumab dose received. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018) | 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 Sponsor's product, 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 the Sponsor's product was also an AE. The number of participants who experienced an AE was reported for each arm. |
| Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology (IRO): Melanoma Participants (Parts B Plus D) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | ORR was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters \[SOD\] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRO was reported as the ORR for each melanoma dose arm (Parts B plus D). |
| ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | ORR was defined as the percentage of participants in the analysis population who had a confirmed CR (disappearance of all lesions) or PR (at least a 30% decrease in the sum of diameters \[SOD\] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRC was reported as the ORR for each NSCLC dose arm (Parts C plus F). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days) | Blood samples were collected at specified intervals for the determination of Cmax. Cmax was defined as the maximum concentration of pembrolizumab reached. Cmax was based on noncompartmental analysis and reported for participants in Parts A and A1. |
| Time to Maximum Concentration (Tmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days) | Blood samples were collected at specified intervals for the determination of Tmax. Tmax was defined as time to the maximum concentration of pembrolizumab reached. Tmax was based on noncompartmental analysis and reported for participants in Parts A and A1. |
| Terminal Half-Life (t ½) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days) | Blood samples were collected at specified intervals for the determination of t½. t½ was defined as the time required to divide the pembrolizumab plasma concentration by two after reaching pseudo-equilibrium, following a single dose of pembrolizumab. t½ was based on noncompartmental analysis and reported for participants in Parts A and A1. |
| Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 21 (AUC 0-21) in Solid Tumor Participants (Part A2) | Cycle 1: Day 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours; Day 5, Day 8: pre- and post-dose; Day 15 (Cycle = 21 days) | Blood samples were collected at specified intervals for the determination of AUC0-21. AUC0-21 was defined as the area under the concentration-time curve of pembrolizumab from time zero to Study Day 21. AUC0-21 was based on noncompartmental analysis and reported for participants in Part A2. |
| Area Under the Concentration-Time Curve of Pembrolizumab From Day 21 to Day 42 (AUC21-42) in Solid Tumor Participants (Part A2) | Cycle 1: Day 21; Cycle 2: Day 1: Pre-dose, post-dose at 0.5 and 24 hours, Day 3, Day 8, Day 15 (Cycle = 21 days) | Blood samples were collected at specified intervals for the determination of AUC21-42. AUC21-42 was defined as the area under the concentration-time curve of pembrolizumab from Study Day 21 (end of Cycle 1) through Study Day 42 (end of Cycle 2). AUC21-42 was based on noncompartmental analysis and reported for participants in Part A2. |
| Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Parts A and A1: pre-dose at Cycles 2, 4, 6, 8, 10, 12, 14 (cycle=14 days); A2 Cohorts: pre-dose at Cycles 2, 3, 5, 7, 9, 11 (cycle=21 days) | Pre-dose samples were collected 24 hours before infusion of pembrolizumab at specified intervals for the determination of Ctrough. Ctrough was defined as the lowest concentration of pembrolizumab reached before the next dose was administered. Ctrough was reported for each Part A arm according to cycle and nominal time after first dose (Day). Results for each cycle reported for arms with N\>1 at that timepoint. Ctrough data for melanoma (Parts B and D) and NSCLC (Parts C and F) participants are presented separately and are not included here. |
| Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Part B arms treated every 3 weeks: pre-dose at Cycles 2,5,9,13,17,25,33 (cycle=21 days); Part B treated every 2 weeks: pre-dose at Cycles 2,3,7,13,19,25,31,37 (cycle=14 days); Part D: pre-dose at Cycles 2,3,6,8,12,16,24,32 (cycle=21 days) | Pre-dose samples were collected 24 hours before infusion of pembrolizumab at specified intervals for the determination of Ctrough. Ctrough was defined as the lowest concentration of pembrolizumab reached before the next dose was administered. For the purposes of the Ctrough analysis, samples were collected and analyzed separately for each Part B and D enrolment cohort, and Ctrough was reported for each cohort according to cycle and nominal time after first dose (Day). Results for each cycle reported for arms with N\>1 at that timepoint. Ctrough data for solid tumor (Part A) and NSCLC (Parts C and F) participants are presented separately and are not included here. |
| Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Part C: pre-dose at Cycles 2,5,9,13,17,21 (cycle=21 days); Part F treated every 3 weeks: pre-dose at Cycles 2,3,6,8,12,14,16,24,32 (cycle=21 days); Part F treated every 2 weeks: pre-dose at Cycles 2,3,6,7,8,9,12,16,18,24,32,36,40,48 (cycle=14 days) | Pre-dose samples were collected 24 hours before infusion of pembrolizumab at specified intervals for the determination of Ctrough. Ctrough was defined as the lowest concentration reached by pembrolizumab before the next dose was administered. For the purposes of the Ctrough analysis, samples were collected and analyzed separately for each Part C and F enrolment cohort, and Ctrough was reported for each cohort according to cycle and nominal time after first dose (Day). Results for each cycle reported for arms with N\>1 at that timepoint. Ctrough data for solid tumor (Part A) and melanoma (Parts B and D) participants are presented separately and are not included here. |
| Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015) | The percent change from baseline in tumor size based on IRC per RECIST 1.1 was reported according to PD-L1 status in Ipi-Exposed and Ipi-Naïve melanoma participants. Tumor PD-L1 status was measured by the tumor proportion score (TPS), which was the percentage of tumor cells identified using IHC analysis that expressed PD-L1. Tumors with ≥1% positive staining for PD-L1 were considered positive. Maximum tumor change was defined as the percent change of the participant's smallest post-baseline tumor size from the baseline. The number of participants in a percent change from baseline range was reported categorically according to PD-L1 status (PD-L1-Positive, PD-L1 Negative, PD-L1 Status Unknown). Negative percent change from baseline values indicate tumor size reduction, with the greatest reduction possible indicated as ≤ -30%. As specified by the protocol, this analysis of melanoma participants was performed according to ipilimumab exposure (Ipi-Exposed and Ipi-Naïve). |
| Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015) | Percent CFB in tumor size based on IRC per RECIST 1.1 was reported according to PD-L1 status in prior treatment-naïve and previously-treated NSCLC participants. Tumor PD-L1 status was measured by TPS, which was the percentage of tumor cells identified using IHC analysis that expressed PD-L1, as follows: TPS ≥50% =tumor strongly positive, TPS of 1%-49% =tumor weakly positive, TPS \<1% =tumor considered negative, or TPS unknown. Maximum tumor change for a participant was defined as the percent change of the participant's smallest post-baseline tumor size from baseline. The number of participants in a percent CFB range was reported categorically according to PD-L1 status (TPS ≥50%, TPS = 1-49%, TPS \<1%, TPS Unknown). Negative percent CFB values indicate tumor size reduction, with the greatest reduction possible indicated as ≤ -30%. As specified by the protocol, analysis of NSCLC participants was performed according to prior treatment exposure (Treatment Naive and Previously Treated). |
| Disease Control Rate (DCR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | DCR was defined as the percentage of participants who had a CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD\]). The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by IRO was reported as the DCR for each melanoma dose arm (Parts B plus D). |
| Duration of Response (DOR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D) | From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months) | For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (At least a 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 progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 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 at least 5 mm. The appearance of one or more new lesions was also considered PD. DOR assessments were based on IRO with confirmation. The DOR according to RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported for each melanoma dose arm (Parts B plus D). |
| ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | ORR was defined as the percentage of participants in the analysis population who had a confirmed immune-related Complete Response (irCR: complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or immune-related Partial Response (irPR: decrease in sum of the products of the two largest perpendicular diameters (SPD) of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC. The percentage of participants who experienced a confirmed irCR or irPR according to irRC as assessed by the investigator was reported as the ORR for each melanoma dose arm (Parts B plus D). |
| Overall Survival (OS) in Melanoma Participants (Parts B Plus D) | Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018) | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. OS was reported for each melanoma dose arm (Parts B plus D). |
| DCR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | DCR according to irRC was defined as the percentage of participants who had a irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions), irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation), or SD (neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for PD \[at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented\]). The percentage of participants who experienced a confirmed CR, PR, or SD according to irRC as assessed by the investigator was reported as the DCR for each melanoma dose arm (Parts B plus D). |
| DOR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months) | For participants who demonstrated a confirmed irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC, DOR was defined as the time from first documented evidence of an irCR or irPR until PD or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. The DOR according to irRC as assessed by the investigator for all participants who experienced a confirmed irCR or irPR was reported for each melanoma dose arm (Parts B plus D). |
| PFS According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. PFS according to irRC as assessed by the investigator was reported for each melanoma dose arm (Parts B plus D). |
| DCR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | DCR was defined as the percentage of participants who had a CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD\]). The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by IRC was reported as the DCR for each NSCLC dose arm (Parts C plus F). |
| DOR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months) | For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 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 censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 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 at least 5 mm. The appearance of one or more new lesions was also considered PD. DOR assessments were based on IRC with confirmation. The DOR according to RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported for each NSCLC dose arm (Parts C plus F). |
| PFS According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | PFS was defined as the time from randomization to the first documented 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. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS according to RECIST 1.1 as assessed by IRC was reported for each NSCLC dose arm (Parts C plus F). |
| OS in NSCLC Participants (Parts C Plus F) | Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018) | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. OS was reported for each NSCLC dose arm (Parts C plus F). |
| DCR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | DCR according to irRC was defined as the percentage of participants who had a irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions), irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation), or SD (neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for PD \[at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented\]). The percentage of participants who experienced a confirmed CR, PR, or SD according to irRC as assessed by the investigator was reported as the DCR for each NSCLC dose arm (Parts C plus F). |
| DOR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months) | For participants who demonstrated a confirmed irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC, DOR was defined as the time from first documented evidence of an irCR or irPR until PD or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. The DOR according to irRC as assessed by the investigator for all participants who experienced a confirmed irCR or irPR was reported for each NSCLC dose arm (Parts C plus F). |
| PFS According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. PFS according to irRC as assessed by the investigator was reported for each NSCLC dose arm (Parts C plus F). |
| Progression Free Survival (PFS) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B Plus D) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | PFS was defined as the time from randomization to the first documented 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. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS according to RECIST 1.1 as assessed by IRO was reported for each melanoma dose arm (Parts B plus D). |
| ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015) | ORR was defined as the percentage of participants in the analysis population who had a confirmed irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or irPR (decrease in sum of the products of the two largest perpendicular diameters (SPD) of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC. The percentage of participants who experienced a confirmed irCR or irPR according to irRC as assessed by the investigator was reported as the ORR for each NSCLC dose arm (Parts C plus F). |
| Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 28 (AUC 0-28) in Solid Tumor Participants (Parts A and A1) | Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days) | Blood samples were collected at specified intervals for the determination of AUC0-28. AUC0-28 was defined as the area under the concentration-time curve of pembrolizumab from time zero to Day 28. AUC0-28 was based on noncompartmental analysis and reported for participants in Parts A and A1. |
| Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (Parts A and A1) | Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days) | Blood samples were collected at specified intervals for the determination of AUC0-inf. AUC0-inf was defined as the area under the concentration-time curve of pembrolizumab from time zero to infinity. AUC0-inf was based on noncompartmental analysis and reported for participants in Parts A and A1. |
Participant flow
Recruitment details
Participants with a histologically- or cytologically-confirmed diagnosis of any type of carcinoma (solid tumors), melanoma (MEL), or non-small cell lung cancer (NSCLC), with progressive locally advanced or metastatic disease, were recruited.
Pre-assignment details
Of 1260 participants enrolled or randomized to the study, 1235 received at least one dose of treatment (All Treated Population) and were evaluable for all safety and efficacy analyses. Part E did not enroll any participants.
Participants by arm
| Arm | Count |
|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2. | 4 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2. | 3 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2. | 12 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2. | 4 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2. | 3 |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2. | 6 |
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. | 164 |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. | 321 |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. | 183 |
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. | 61 |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. | 296 |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. | 203 |
| Total | 1,260 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 2 | 1 | 1 | 4 | 15 | 49 | 22 | 7 | 50 | 21 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 3 | 0 | 1 | 0 | 4 | 8 | 7 | 4 | 7 | 3 | 0 | 0 | 0 |
| Overall Study | Not Reported | 0 | 0 | 0 | 1 | 0 | 0 | 24 | 58 | 41 | 2 | 23 | 13 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 2 | 1 | 5 | 2 | 0 | 1 | 87 | 144 | 85 | 40 | 175 | 136 | 0 | 0 | 0 |
| Overall Study | Screen Failure | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 2 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 | 0 | 0 | 1 | 13 | 35 | 11 | 2 | 18 | 13 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 71.0 Years STANDARD_DEVIATION 6.4 | 76.0 Years STANDARD_DEVIATION 8.7 | 62.7 Years STANDARD_DEVIATION 16.1 | 53.8 Years STANDARD_DEVIATION 11.7 | 53.3 Years STANDARD_DEVIATION 23.5 | 69.0 Years STANDARD_DEVIATION 7.6 | 57.9 Years STANDARD_DEVIATION 13.5 | 60.5 Years STANDARD_DEVIATION 13.5 | 60.1 Years STANDARD_DEVIATION 14.4 | 61.9 Years STANDARD_DEVIATION 11 | 61.8 Years STANDARD_DEVIATION 11.2 | 63.0 Years STANDARD_DEVIATION 10.2 | 61.0 Years STANDARD_DEVIATION 12.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 12 Participants | 13 Participants | 3 Participants | 1 Participants | 20 Participants | 8 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 9 Participants | 4 Participants | 3 Participants | 6 Participants | 152 Participants | 308 Participants | 180 Participants | 60 Participants | 274 Participants | 195 Participants | 1195 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 6 Participants | 2 Participants | 6 Participants | 46 Participants | 19 Participants | 81 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 12 Participants | 8 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 12 Participants | 4 Participants | 2 Participants | 6 Participants | 161 Participants | 310 Participants | 178 Participants | 53 Participants | 237 Participants | 174 Participants | 1144 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 69 Participants | 125 Participants | 122 Participants | 29 Participants | 145 Participants | 91 Participants | 589 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 9 Participants | 4 Participants | 3 Participants | 6 Participants | 95 Participants | 196 Participants | 61 Participants | 32 Participants | 151 Participants | 112 Participants | 671 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 | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 4 | 1 / 3 | 6 / 12 | 2 / 4 | 1 / 3 | 5 / 6 | 111 / 164 | 213 / 321 | 110 / 183 | 52 / 61 | 240 / 296 | 166 / 203 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 8 / 10 | 4 / 4 | 3 / 3 | 5 / 6 | 158 / 162 | 303 / 313 | 175 / 180 | 55 / 61 | 271 / 287 | 191 / 202 |
| serious Total, serious adverse events | 1 / 4 | 1 / 3 | 3 / 10 | 0 / 4 | 2 / 3 | 2 / 6 | 69 / 162 | 129 / 313 | 79 / 180 | 34 / 61 | 119 / 287 | 86 / 202 |
Outcome results
Primary
Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) in Participants With Solid Tumors (Parts A and A1)
DLTs were assessed according to NCI-CTCAE v.4.0 during the first cycle (28 days) and were defined as occurrence of any of the following toxicities if judged by the investigator to be possibly, probably or definitely related to study drug administration: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥14 days; Gr 3 nonhematologic toxicity lasting \>3 days despite optimal supportive care; any Grade 3 non-hematologic laboratory value if medical intervention was required to treat the participant, the abnormality led to hospitalization, or the abnormality persisted for \>1 week; Gr 3 or 4 febrile neutropenia; thrombocytopenia \<25,000 cells/mm\^3 (if associated with a bleeding event requiring an elective platelet transfusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to an Intensive Care Unit); or Gr 5 toxicity. The number of participants in Part A and Part A1 with a DLT were reported by pembrolizumab dose received.
Time frame: Up to 28 days in Cycle 1
Population: All participants in Parts A and A1 who received ≥1 dose of study treatment and either 1) had a DLT in Cycle 1 or 2) received ≥90% of the prescribed dose of pembrolizumab in Cycle 1 and completed all safety evaluations ≥28 days after the first administration of pembrolizumab without experiencing DLT. Per protocol, Parts A2 and B-F were not analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) in Participants With Solid Tumors (Parts A and A1) | 0 Participants |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) in Participants With Solid Tumors (Parts A and A1) | 0 Participants |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) in Participants With Solid Tumors (Parts A and A1) | 0 Participants |
Primary
Number of Participants Who Experienced an Adverse Event (AE)
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 Sponsor's product, 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 the Sponsor's product was also an AE. The number of participants who experienced an AE was reported for each arm.
Time frame: Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
Population: All participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Number of Participants Who Experienced an Adverse Event (AE) | 4 Participants |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Number of Participants Who Experienced an Adverse Event (AE) | 3 Participants |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Number of Participants Who Experienced an Adverse Event (AE) | 9 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Number of Participants Who Experienced an Adverse Event (AE) | 4 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Number of Participants Who Experienced an Adverse Event (AE) | 3 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Number of Participants Who Experienced an Adverse Event (AE) | 6 Participants |
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Number of Participants Who Experienced an Adverse Event (AE) | 161 Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Number of Participants Who Experienced an Adverse Event (AE) | 308 Participants |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | Number of Participants Who Experienced an Adverse Event (AE) | 178 Participants |
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | Number of Participants Who Experienced an Adverse Event (AE) | 60 Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | Number of Participants Who Experienced an Adverse Event (AE) | 277 Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | Number of Participants Who Experienced an Adverse Event (AE) | 198 Participants |
Primary
ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F)
ORR was defined as the percentage of participants in the analysis population who had a confirmed CR (disappearance of all lesions) or PR (at least a 30% decrease in the sum of diameters \[SOD\] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRC was reported as the ORR for each NSCLC dose arm (Parts C plus F).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F) | 19.7 Percentage of Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F) | 21.6 Percentage of Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F) | 19.3 Percentage of Participants |
Primary
Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology (IRO): Melanoma Participants (Parts B Plus D)
ORR was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters \[SOD\] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRO was reported as the ORR for each melanoma dose arm (Parts B plus D).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology (IRO): Melanoma Participants (Parts B Plus D) | 30.2 Percentage of Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology (IRO): Melanoma Participants (Parts B Plus D) | 29.4 Percentage of Participants |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology (IRO): Melanoma Participants (Parts B Plus D) | 36.7 Percentage of Participants |
Secondary
Area Under the Concentration-Time Curve of Pembrolizumab From Day 21 to Day 42 (AUC21-42) in Solid Tumor Participants (Part A2)
Blood samples were collected at specified intervals for the determination of AUC21-42. AUC21-42 was defined as the area under the concentration-time curve of pembrolizumab from Study Day 21 (end of Cycle 1) through Study Day 42 (end of Cycle 2). AUC21-42 was based on noncompartmental analysis and reported for participants in Part A2.
Time frame: Cycle 1: Day 21; Cycle 2: Day 1: Pre-dose, post-dose at 0.5 and 24 hours, Day 3, Day 8, Day 15 (Cycle = 21 days)
Population: All participants in Part A2 receiving escalating doses of drug during Cycle 1 and having available AUC21-42 data during Cycle 2. Two participants were excluded from analysis due to discontinuation. Per protocol, participants in Parts A, A1, B, C, D, C, and F were not included in the escalating dose PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Area Under the Concentration-Time Curve of Pembrolizumab From Day 21 to Day 42 (AUC21-42) in Solid Tumor Participants (Part A2) | 486 μg•day/mL | Geometric Coefficient of Variation 16 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Area Under the Concentration-Time Curve of Pembrolizumab From Day 21 to Day 42 (AUC21-42) in Solid Tumor Participants (Part A2) | 348 μg•day/mL | Geometric Coefficient of Variation 18 |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Area Under the Concentration-Time Curve of Pembrolizumab From Day 21 to Day 42 (AUC21-42) in Solid Tumor Participants (Part A2) | 2280 μg•day/mL | Geometric Coefficient of Variation 24 |
Secondary
Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 21 (AUC 0-21) in Solid Tumor Participants (Part A2)
Blood samples were collected at specified intervals for the determination of AUC0-21. AUC0-21 was defined as the area under the concentration-time curve of pembrolizumab from time zero to Study Day 21. AUC0-21 was based on noncompartmental analysis and reported for participants in Part A2.
Time frame: Cycle 1: Day 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours; Day 5, Day 8: pre- and post-dose; Day 15 (Cycle = 21 days)
Population: All participants in Part A2 receiving escalating doses of drug during Cycle 1 (21 days) and having available AUC0-21 data. One participant was excluded from analysis due to discontinuation. Per protocol, participants in Parts A, A1, B, C, D, C, and F were not included in the escalating dose PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 21 (AUC 0-21) in Solid Tumor Participants (Part A2) | 57.1 μg•day/mL | Geometric Coefficient of Variation 21 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 21 (AUC 0-21) in Solid Tumor Participants (Part A2) | 50.4 μg•day/mL | Geometric Coefficient of Variation 28 |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 21 (AUC 0-21) in Solid Tumor Participants (Part A2) | 186 μg•day/mL | Geometric Coefficient of Variation 28 |
Secondary
Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 28 (AUC 0-28) in Solid Tumor Participants (Parts A and A1)
Blood samples were collected at specified intervals for the determination of AUC0-28. AUC0-28 was defined as the area under the concentration-time curve of pembrolizumab from time zero to Day 28. AUC0-28 was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time frame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Population: All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available AUC0-28 data. Two participants were excluded from analysis due to discontinuation. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose pharmacokinetic (PK) analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 28 (AUC 0-28) in Solid Tumor Participants (Parts A and A1) | 157 μg•day/mL | Geometric Coefficient of Variation 16 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 28 (AUC 0-28) in Solid Tumor Participants (Parts A and A1) | 955 μg•day/mL | Geometric Coefficient of Variation 23 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 28 (AUC 0-28) in Solid Tumor Participants (Parts A and A1) | 2160 μg•day/mL | Geometric Coefficient of Variation 31 |
Secondary
Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (Parts A and A1)
Blood samples were collected at specified intervals for the determination of AUC0-inf. AUC0-inf was defined as the area under the concentration-time curve of pembrolizumab from time zero to infinity. AUC0-inf was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time frame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Population: All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available AUC0-inf data. Two participants were excluded from analysis due to discontinuation. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (Parts A and A1) | 212 μg•day/mL | Geometric Coefficient of Variation 36 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (Parts A and A1) | 1530 μg•day/mL | Geometric Coefficient of Variation 28 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (Parts A and A1) | 3230 μg•day/mL | Geometric Coefficient of Variation 44 |
Secondary
Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D)
Pre-dose samples were collected 24 hours before infusion of pembrolizumab at specified intervals for the determination of Ctrough. Ctrough was defined as the lowest concentration of pembrolizumab reached before the next dose was administered. For the purposes of the Ctrough analysis, samples were collected and analyzed separately for each Part B and D enrolment cohort, and Ctrough was reported for each cohort according to cycle and nominal time after first dose (Day). Results for each cycle reported for arms with N\>1 at that timepoint. Ctrough data for solid tumor (Part A) and NSCLC (Parts C and F) participants are presented separately and are not included here.
Time frame: Part B arms treated every 3 weeks: pre-dose at Cycles 2,5,9,13,17,25,33 (cycle=21 days); Part B treated every 2 weeks: pre-dose at Cycles 2,3,7,13,19,25,31,37 (cycle=14 days); Part D: pre-dose at Cycles 2,3,6,8,12,16,24,32 (cycle=21 days)
Population: All melanoma participants receiving ≥1 dose of drug and having available samples collected pre-dose before each cycle. Per protocol, Ctrough analyzed separately by Part, dose, and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms (indicated by zero participants analyzed entered in the table).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 9 (Day 168 ) | 25.5 µg/mL | Geometric Coefficient of Variation 59.6 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 13 (Day 252) | 27.2 µg/mL | Geometric Coefficient of Variation 50.4 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 33 (Day 672) | 31.4 µg/mL | Geometric Coefficient of Variation 34 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 2 (Day 21) | 8.69 µg/mL | Geometric Coefficient of Variation 48.9 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 25 (Day 504) | 29.3 µg/mL | Geometric Coefficient of Variation 42.4 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 5 (Day 84) | 19.5 µg/mL | Geometric Coefficient of Variation 58.3 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 17 (Day 336) | 31.4 µg/mL | Geometric Coefficient of Variation 48.9 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 25 (Day 504) | 165 µg/mL | Geometric Coefficient of Variation 41.4 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 9 (Day 168 ) | 161 µg/mL | Geometric Coefficient of Variation 38.4 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 13 (Day 252) | 153 µg/mL | Geometric Coefficient of Variation 39.6 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 5 (Day 84) | 119 µg/mL | Geometric Coefficient of Variation 50.7 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 2 (Day 21) | 48.5 µg/mL | Geometric Coefficient of Variation 37.9 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 24 (Day 483) | 152 µg/mL | Geometric Coefficient of Variation 7.5 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 33 (Day 672) | 166 µg/mL | Geometric Coefficient of Variation 37.7 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 12 (Day 231) | 193 µg/mL | Geometric Coefficient of Variation 21.1 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 17 (Day 336) | 168 µg/mL | Geometric Coefficient of Variation 48.5 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 7 (Day 126) | 89.2 µg/mL | Geometric Coefficient of Variation 34.4 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 8 (Day 147) | 166 µg/mL | Geometric Coefficient of Variation 5.1 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 3 (Day 42) | 80.3 µg/mL | Geometric Coefficient of Variation 1.2 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 49 (Day 672) | 255 µg/mL | Geometric Coefficient of Variation 42.6 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 3 (Day 28) | 94.0 µg/mL | Geometric Coefficient of Variation 47.2 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 7 (Day 84) | 173 µg/mL | Geometric Coefficient of Variation 49.7 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 13 (Day 168) | 232 µg/mL | Geometric Coefficient of Variation 44.1 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 18 (Day 238) | 171 µg/mL | Geometric Coefficient of Variation 27.7 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 19 (Day 252) | 253 µg/mL | Geometric Coefficient of Variation 37.5 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 24 (Day 322) | 246 µg/mL | Geometric Coefficient of Variation 18.2 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 25 (Day 336) | 242 µg/mL | Geometric Coefficient of Variation 39.9 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 31 (Day 420) | 184 µg/mL | Geometric Coefficient of Variation 29.2 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 33 (Day 448) | 80.0 µg/mL | Geometric Coefficient of Variation 57.9 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 37 (Day 504) | 232 µg/mL | Geometric Coefficient of Variation 63.8 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 48 (Day 658) | 169 µg/mL | Geometric Coefficient of Variation 25.3 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 2 (Day 14) | 63.7 µg/mL | Geometric Coefficient of Variation 13.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 6 (Day 105) | 25.3 µg/mL | Geometric Coefficient of Variation 52.4 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 12 (Day 231) | 29.3 µg/mL | Geometric Coefficient of Variation 34.7 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 24 (Day 483) | 30.3 µg/mL | Geometric Coefficient of Variation 40.1 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 3 (Day 42) | 16.8 µg/mL | Geometric Coefficient of Variation 57.2 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 16 (Day 315) | 30.5 µg/mL | Geometric Coefficient of Variation 50.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 32 (Day 651) | 23.0 µg/mL | Geometric Coefficient of Variation 44.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 2 (Day 21) | 10.1 µg/mL | Geometric Coefficient of Variation 56.3 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 8 (Day 147) | 23.5 µg/mL | Geometric Coefficient of Variation 50.1 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 2 (Day 21) | 62.6 µg/mL | Geometric Coefficient of Variation 37.2 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 12 (Day 231) | 173 µg/mL | Geometric Coefficient of Variation 38.9 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 17 (Day 336) | 157 µg/mL | Geometric Coefficient of Variation 47 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 32 (Day 651) | 155 µg/mL | Geometric Coefficient of Variation 38.5 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 24 (Day 483) | 147 µg/mL | Geometric Coefficient of Variation 47 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 6 (Day 105) | 132 µg/mL | Geometric Coefficient of Variation 45.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 3 (Day 42) | 94.3 µg/mL | Geometric Coefficient of Variation 37.1 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 8 (Day 147) | 152 µg/mL | Geometric Coefficient of Variation 40.7 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) | Cycle 16 (Day 315) | 183 µg/mL | Geometric Coefficient of Variation 37.8 |
Secondary
Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F)
Pre-dose samples were collected 24 hours before infusion of pembrolizumab at specified intervals for the determination of Ctrough. Ctrough was defined as the lowest concentration reached by pembrolizumab before the next dose was administered. For the purposes of the Ctrough analysis, samples were collected and analyzed separately for each Part C and F enrolment cohort, and Ctrough was reported for each cohort according to cycle and nominal time after first dose (Day). Results for each cycle reported for arms with N\>1 at that timepoint. Ctrough data for solid tumor (Part A) and melanoma (Parts B and D) participants are presented separately and are not included here.
Time frame: Part C: pre-dose at Cycles 2,5,9,13,17,21 (cycle=21 days); Part F treated every 3 weeks: pre-dose at Cycles 2,3,6,8,12,14,16,24,32 (cycle=21 days); Part F treated every 2 weeks: pre-dose at Cycles 2,3,6,7,8,9,12,16,18,24,32,36,40,48 (cycle=14 days)
Population: All NSCLC participants receiving ≥1 dose of drug and having available samples collected pre-dose before each cycle. Per protocol, Ctrough analyzed separately by Part, dose, and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms (indicated by zero participants analyzed entered in the table).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 5 (Day 84) | 136 µg/mL | Geometric Coefficient of Variation 29.6 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 17 (Day 336) | 184 µg/mL | Geometric Coefficient of Variation 34.8 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 13 (Day 252) | 197 µg/mL | Geometric Coefficient of Variation 47.1 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 2 (Day 21) | 52.0 µg/mL | Geometric Coefficient of Variation 31.7 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 21 (Day 420) | 167 µg/mL | Geometric Coefficient of Variation 40.2 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 25 (Day 504) | 207 µg/mL | Geometric Coefficient of Variation 67.9 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 29 (Day 588) | 173 µg/mL | Geometric Coefficient of Variation 39 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 9 (Day 168) | 168 µg/mL | Geometric Coefficient of Variation 26.3 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 32 (Day 651) | 30.5 µg/mL | Geometric Coefficient of Variation 11.6 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 8 (Day 147) | 20.6 µg/mL | Geometric Coefficient of Variation 46.2 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 2 (Day 21) | 8.23 µg/mL | Geometric Coefficient of Variation 41.1 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 33 (Day 672) | 40.6 µg/mL | Geometric Coefficient of Variation 32.5 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 12 (Day 231) | 20.0 µg/mL | Geometric Coefficient of Variation 60.1 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 24 (Day 483) | 24.3 µg/mL | Geometric Coefficient of Variation 26 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 3 (Day 42) | 11.8 µg/mL | Geometric Coefficient of Variation 62.1 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 16 (Day 315) | 23.3 µg/mL | Geometric Coefficient of Variation 29.1 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 6 (Day 105) | 18.3 µg/mL | Geometric Coefficient of Variation 40.8 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 29 (Day 588) | 32.9 µg/mL | Geometric Coefficient of Variation 13.2 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 20 (Day 266) | 215 µg/mL | Geometric Coefficient of Variation 0.98 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 3 (Day 28) | 89.3 µg/mL | Geometric Coefficient of Variation 39.4 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 4 (Day 42) | 173 µg/mL | Geometric Coefficient of Variation 36.3 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 6 (Day 70) | 149 µg/mL | Geometric Coefficient of Variation 40.6 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 7 (Day 84) | 159 µg/mL | Geometric Coefficient of Variation 19.5 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 8 (Day 98) | 180 µg/mL | Geometric Coefficient of Variation 42.1 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 9 (Day 112) | 145 µg/mL | Geometric Coefficient of Variation 44.7 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 12 (Day 154) | 206 µg/mL | Geometric Coefficient of Variation 42.6 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 16 (Day 210) | 205 µg/mL | Geometric Coefficient of Variation 46 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 18 (Day 238) | 214 µg/mL | Geometric Coefficient of Variation 34.7 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 2 (Day 14) | 55.0 µg/mL | Geometric Coefficient of Variation 33.8 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 22 (Day 294) | 209 µg/mL | Geometric Coefficient of Variation 17.9 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 24 (Day 322) | 234 µg/mL | Geometric Coefficient of Variation 33.5 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 26 (Day 350) | 202 µg/mL | Geometric Coefficient of Variation 13.2 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 28 (Day 378) | 140 µg/mL | Geometric Coefficient of Variation 33.5 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 30 (Day 406) | 149 µg/mL | Geometric Coefficient of Variation 16.2 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 32 (Day 434) | 244 µg/mL | Geometric Coefficient of Variation 47.7 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 36 (Day 490) | 221 µg/mL | Geometric Coefficient of Variation 39.9 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 40 (Day 546) | 219 µg/mL | Geometric Coefficient of Variation 52.2 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 48 (Day 658) | 206 µg/mL | Geometric Coefficient of Variation 111.2 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 3 (Day 42) | 67.9 µg/mL | Geometric Coefficient of Variation 45.5 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 12 (Day 231) | 125 µg/mL | Geometric Coefficient of Variation 41.3 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 24 (Day 483) | 137 µg/mL | Geometric Coefficient of Variation 43.4 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 32 (Day 651) | 141 µg/mL | Geometric Coefficient of Variation 49.8 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 9 (Day 168) | 96.8 µg/mL | Geometric Coefficient of Variation 47.2 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 16 (Day 315) | 124 µg/mL | Geometric Coefficient of Variation 48.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 2 (Day 21) | 43.6 µg/mL | Geometric Coefficient of Variation 42.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 18 (Day 357) | 105 µg/mL | Geometric Coefficient of Variation 48.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 8 (Day 147) | 118 µg/mL | Geometric Coefficient of Variation 51.3 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 20 (Day 399) | 81.9 µg/mL | Geometric Coefficient of Variation 74.5 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 6 (Day 105) | 99.7 µg/mL | Geometric Coefficient of Variation 53.9 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) | Cycle 14 (Day 273) | 121 µg/mL | Geometric Coefficient of Variation 56.6 |
Secondary
DCR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
DCR according to irRC was defined as the percentage of participants who had a irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions), irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation), or SD (neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for PD \[at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented\]). The percentage of participants who experienced a confirmed CR, PR, or SD according to irRC as assessed by the investigator was reported as the DCR for each melanoma dose arm (Parts B plus D).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | DCR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | 62.3 Percentage of Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | DCR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | 62.6 Percentage of Participants |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | DCR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | 69.4 Percentage of Participants |
Secondary
DCR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
DCR according to irRC was defined as the percentage of participants who had a irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions), irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation), or SD (neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for PD \[at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented\]). The percentage of participants who experienced a confirmed CR, PR, or SD according to irRC as assessed by the investigator was reported as the DCR for each NSCLC dose arm (Parts C plus F).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | DCR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | 57.4 Percentage of Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | DCR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | 62.7 Percentage of Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | DCR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | 65.3 Percentage of Participants |
Secondary
DCR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)
DCR was defined as the percentage of participants who had a CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD\]). The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by IRC was reported as the DCR for each NSCLC dose arm (Parts C plus F).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | DCR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | 50.8 Percentage of Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | DCR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | 51.6 Percentage of Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | DCR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | 49.0 Percentage of Participants |
Secondary
Disease Control Rate (DCR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D)
DCR was defined as the percentage of participants who had a CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD\]). The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by IRO was reported as the DCR for each melanoma dose arm (Parts B plus D).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Disease Control Rate (DCR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D) | 48.1 Percentage of Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Disease Control Rate (DCR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D) | 47.6 Percentage of Participants |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | Disease Control Rate (DCR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D) | 56.1 Percentage of Participants |
Secondary
DOR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
For participants who demonstrated a confirmed irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC, DOR was defined as the time from first documented evidence of an irCR or irPR until PD or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. The DOR according to irRC as assessed by the investigator for all participants who experienced a confirmed irCR or irPR was reported for each melanoma dose arm (Parts B plus D).
Time frame: From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
Population: All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment and who demonstrated a confirmed irRC response (irCR or irPR). Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | DOR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | NA Months |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | DOR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | NA Months |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | DOR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | NA Months |
Secondary
DOR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
For participants who demonstrated a confirmed irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC, DOR was defined as the time from first documented evidence of an irCR or irPR until PD or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. The DOR according to irRC as assessed by the investigator for all participants who experienced a confirmed irCR or irPR was reported for each NSCLC dose arm (Parts C plus F).
Time frame: From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
Population: All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment and who demonstrated a confirmed response (CR or PR). Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B and D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | DOR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | NA Months |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | DOR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | NA Months |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | DOR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | NA Months |
Secondary
DOR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 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 censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 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 at least 5 mm. The appearance of one or more new lesions was also considered PD. DOR assessments were based on IRC with confirmation. The DOR according to RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported for each NSCLC dose arm (Parts C plus F).
Time frame: From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
Population: All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment and who demonstrated a confirmed response (CR or PR). Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B and D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | DOR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | NA Months |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | DOR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | NA Months |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | DOR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | 20.7 Months |
Secondary
Duration of Response (DOR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D)
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (At least a 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 progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 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 at least 5 mm. The appearance of one or more new lesions was also considered PD. DOR assessments were based on IRO with confirmation. The DOR according to RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported for each melanoma dose arm (Parts B plus D).
Time frame: From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
Population: All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment and who demonstrated a confirmed response (CR or PR). Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Duration of Response (DOR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D) | NA Weeks |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Duration of Response (DOR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D) | NA Weeks |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | Duration of Response (DOR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D) | NA Weeks |
Secondary
Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2)
Pre-dose samples were collected 24 hours before infusion of pembrolizumab at specified intervals for the determination of Ctrough. Ctrough was defined as the lowest concentration of pembrolizumab reached before the next dose was administered. Ctrough was reported for each Part A arm according to cycle and nominal time after first dose (Day). Results for each cycle reported for arms with N\>1 at that timepoint. Ctrough data for melanoma (Parts B and D) and NSCLC (Parts C and F) participants are presented separately and are not included here.
Time frame: Parts A and A1: pre-dose at Cycles 2, 4, 6, 8, 10, 12, 14 (cycle=14 days); A2 Cohorts: pre-dose at Cycles 2, 3, 5, 7, 9, 11 (cycle=21 days)
Population: All Part A participants receiving ≥1 dose of drug and having available Ctrough samples collected pre-dose before each cycle. Due to differing dosing schedules or N\<1, some time points were not applicable for certain arms if data were not collected or analyzed (indicated by zero participants analyzed entered in the table).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 6 (Day 84) | 9.93 μg/mL | Geometric Coefficient of Variation 5.6 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 4 (Day 56) | 6.45 μg/mL | Geometric Coefficient of Variation 13 |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 2 (Day 28) | 2.19 μg/mL | Geometric Coefficient of Variation 62.4 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 14 (Day 196) | 54.1 μg/mL | Geometric Coefficient of Variation 4.3 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 8 (Day 112) | 66.8 μg/mL | Geometric Coefficient of Variation 11.1 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 6 (Day 84) | 55.2 μg/mL | Geometric Coefficient of Variation 33.8 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 2 (Day 28) | 18.8 μg/mL | Geometric Coefficient of Variation 42.1 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 10 (Day 140) | 63.0 μg/mL | Geometric Coefficient of Variation 29.8 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 4 (Day 56) | 50.0 μg/mL | Geometric Coefficient of Variation 36.9 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 12 (Day 168) | 62.8 μg/mL | Geometric Coefficient of Variation 1.7 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 8 (Day 112) | 260 μg/mL | Geometric Coefficient of Variation 1.4 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 4 (Day 56) | 122 μg/mL | Geometric Coefficient of Variation 37.2 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 10 (Day 140) | 200 μg/mL | Geometric Coefficient of Variation 4.9 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 6 (Day 84) | 168 μg/mL | Geometric Coefficient of Variation 49.5 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 2 (Day 28) | 41.7 μg/mL | Geometric Coefficient of Variation 44.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 2 (Day 21) | 2.3 μg/mL | Geometric Coefficient of Variation 46.2 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 3 (Day 42) | 10.6 μg/mL | Geometric Coefficient of Variation 15.9 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 5 (Day 84) | 14.8 μg/mL | Geometric Coefficient of Variation 33.4 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 7 (Day 126) | 29.9 μg/mL | Geometric Coefficient of Variation 7.3 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 9 (Day 168) | 29.8 μg/mL | Geometric Coefficient of Variation 1 |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 11 (Day 210) | 40.7 μg/mL | Geometric Coefficient of Variation 38.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 7 (Day 126) | 22.1 μg/mL | Geometric Coefficient of Variation 49.2 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 3 (Day 42) | 11.1 μg/mL | Geometric Coefficient of Variation 28.9 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 5 (Day 84) | 18.3 μg/mL | Geometric Coefficient of Variation 34.1 |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 2 (Day 21) | 1.9 μg/mL | Geometric Coefficient of Variation 19.9 |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 11 (Day 210) | 179 μg/mL | Geometric Coefficient of Variation 37.8 |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 9 (Day 168) | 150 μg/mL | Geometric Coefficient of Variation 29.4 |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 2 (Day 21) | 7.77 μg/mL | Geometric Coefficient of Variation 46.1 |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 7 (Day 126) | 151 μg/mL | Geometric Coefficient of Variation 48 |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 3 (Day 42) | 70.1 μg/mL | Geometric Coefficient of Variation 15.6 |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) | Cycle 5 (Day 84) | 126 μg/mL | Geometric Coefficient of Variation 53.9 |
Secondary
Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F)
Percent CFB in tumor size based on IRC per RECIST 1.1 was reported according to PD-L1 status in prior treatment-naïve and previously-treated NSCLC participants. Tumor PD-L1 status was measured by TPS, which was the percentage of tumor cells identified using IHC analysis that expressed PD-L1, as follows: TPS ≥50% =tumor strongly positive, TPS of 1%-49% =tumor weakly positive, TPS \<1% =tumor considered negative, or TPS unknown. Maximum tumor change for a participant was defined as the percent change of the participant's smallest post-baseline tumor size from baseline. The number of participants in a percent CFB range was reported categorically according to PD-L1 status (TPS ≥50%, TPS = 1-49%, TPS \<1%, TPS Unknown). Negative percent CFB values indicate tumor size reduction, with the greatest reduction possible indicated as ≤ -30%. As specified by the protocol, analysis of NSCLC participants was performed according to prior treatment exposure (Treatment Naive and Previously Treated).
Time frame: Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015)
Population: NSCLC participants that received ≥1 dose of study treatment, had a valid PD-L1 expression measurement, and had both baseline and post-baseline tumor assessments. Per protocol, Part A was not analyzed for biomarker analysis. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 16 Participants |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 0 Participants |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 7 Participants |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 20 Participants |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 4 Participants |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 15 Participants |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 2 Participants |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 2 Participants |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 6 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 1 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 4 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 4 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 37 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 37 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 7 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 32 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 58 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 20 Participants |
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 42 Participants |
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 30 Participants |
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 65 Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 38 Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 15 Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 13 Participants |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 14 Participants |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 14 Participants |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 10 Participants |
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≤ -30% CFB | 129 Participants |
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with ≥ 20% CFB | 73 Participants |
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F) | Number of Participants with > -30% to <20% CFB | 149 Participants |
Secondary
Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D)
The percent change from baseline in tumor size based on IRC per RECIST 1.1 was reported according to PD-L1 status in Ipi-Exposed and Ipi-Naïve melanoma participants. Tumor PD-L1 status was measured by the tumor proportion score (TPS), which was the percentage of tumor cells identified using IHC analysis that expressed PD-L1. Tumors with ≥1% positive staining for PD-L1 were considered positive. Maximum tumor change was defined as the percent change of the participant's smallest post-baseline tumor size from the baseline. The number of participants in a percent change from baseline range was reported categorically according to PD-L1 status (PD-L1-Positive, PD-L1 Negative, PD-L1 Status Unknown). Negative percent change from baseline values indicate tumor size reduction, with the greatest reduction possible indicated as ≤ -30%. As specified by the protocol, this analysis of melanoma participants was performed according to ipilimumab exposure (Ipi-Exposed and Ipi-Naïve).
Time frame: Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015)
Population: Melanoma participants that received ≥1 dose of study treatment, had a valid PD-L1 expression measurement, and had both baseline and post-baseline tumor assessments. Per protocol, Part A was not analyzed for biomarker analysis. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≤ -30% CFB | 93 Participants |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≥ 20% CFB | 26 Participants |
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with > -30% to <20% CFB | 57 Participants |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≥ 20% CFB | 12 Participants |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with > -30% to <20% CFB | 17 Participants |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≤ -30% CFB | 8 Participants |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≥ 20% CFB | 8 Participants |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≤ -30% CFB | 25 Participants |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with > -30% to <20% CFB | 14 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≤ -30% CFB | 126 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with > -30% to <20% CFB | 88 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≥ 20% CFB | 46 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with > -30% to <20% CFB | 32 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≤ -30% CFB | 94 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≥ 20% CFB | 14 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with > -30% to <20% CFB | 10 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≤ -30% CFB | 22 Participants |
| Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≥ 20% CFB | 18 Participants |
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with > -30% to <20% CFB | 11 Participants |
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≤ -30% CFB | 35 Participants |
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≥ 20% CFB | 15 Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≤ -30% CFB | 151 Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with > -30% to <20% CFB | 53 Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D) | Number of Participants with ≥ 20% CFB | 47 Participants |
Secondary
Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)
Blood samples were collected at specified intervals for the determination of Cmax. Cmax was defined as the maximum concentration of pembrolizumab reached. Cmax was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time frame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Population: All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available Cmax data. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | 16.4 μg/mL | Geometric Coefficient of Variation 22 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | 107 μg/mL | Geometric Coefficient of Variation 26 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | 256 μg/mL | Geometric Coefficient of Variation 37 |
Secondary
ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
ORR was defined as the percentage of participants in the analysis population who had a confirmed immune-related Complete Response (irCR: complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or immune-related Partial Response (irPR: decrease in sum of the products of the two largest perpendicular diameters (SPD) of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC. The percentage of participants who experienced a confirmed irCR or irPR according to irRC as assessed by the investigator was reported as the ORR for each melanoma dose arm (Parts B plus D).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | 35.2 Percentage of Participants |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | 39.9 Percentage of Participants |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | 45.6 Percentage of Participants |
Secondary
ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
ORR was defined as the percentage of participants in the analysis population who had a confirmed irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or irPR (decrease in sum of the products of the two largest perpendicular diameters (SPD) of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC. The percentage of participants who experienced a confirmed irCR or irPR according to irRC as assessed by the investigator was reported as the ORR for each NSCLC dose arm (Parts C plus F).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | 23.0 Percentage of Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | 28.9 Percentage of Participants |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | 22.3 Percentage of Participants |
Secondary
OS in NSCLC Participants (Parts C Plus F)
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. OS was reported for each NSCLC dose arm (Parts C plus F).
Time frame: Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
Population: All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | OS in NSCLC Participants (Parts C Plus F) | 8.9 Months |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | OS in NSCLC Participants (Parts C Plus F) | 13.1 Months |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | OS in NSCLC Participants (Parts C Plus F) | 13.4 Months |
Secondary
Overall Survival (OS) in Melanoma Participants (Parts B Plus D)
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. OS was reported for each melanoma dose arm (Parts B plus D).
Time frame: Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
Population: All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Overall Survival (OS) in Melanoma Participants (Parts B Plus D) | 23.1 Months |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Overall Survival (OS) in Melanoma Participants (Parts B Plus D) | 22.5 Months |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | Overall Survival (OS) in Melanoma Participants (Parts B Plus D) | 26.8 Months |
Secondary
PFS According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. PFS according to irRC as assessed by the investigator was reported for each melanoma dose arm (Parts B plus D).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | PFS According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | 8.2 Months |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | PFS According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | 6.6 Months |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | PFS According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) | 9.6 Months |
Secondary
PFS According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. PFS according to irRC as assessed by the investigator was reported for each NSCLC dose arm (Parts C plus F).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | PFS According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | 4.3 Months |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | PFS According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | 4.4 Months |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | PFS According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) | 5.6 Months |
Secondary
PFS According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)
PFS was defined as the time from randomization to the first documented 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. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS according to RECIST 1.1 as assessed by IRC was reported for each NSCLC dose arm (Parts C plus F).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) | PFS According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | 3.3 Months |
| NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) | PFS According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | 3.7 Months |
| NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) | PFS According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) | 3.4 Months |
Secondary
Progression Free Survival (PFS) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B Plus D)
PFS was defined as the time from randomization to the first documented 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. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS according to RECIST 1.1 as assessed by IRO was reported for each melanoma dose arm (Parts B plus D).
Time frame: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Population: All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) | Progression Free Survival (PFS) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B Plus D) | 4.9 Months |
| MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) | Progression Free Survival (PFS) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B Plus D) | 3.7 Months |
| MEL: Pembrolizumab 10 mg/kg Q2W (Part B) | Progression Free Survival (PFS) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B Plus D) | 5.6 Months |
Secondary
Terminal Half-Life (t ½) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)
Blood samples were collected at specified intervals for the determination of t½. t½ was defined as the time required to divide the pembrolizumab plasma concentration by two after reaching pseudo-equilibrium, following a single dose of pembrolizumab. t½ was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time frame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Population: All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available t½ data. Two participants were excluded from analysis due to discontinuation. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Terminal Half-Life (t ½) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | 14.1 days | Geometric Coefficient of Variation 51 |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Terminal Half-Life (t ½) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | 21.6 days | Geometric Coefficient of Variation 10 |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Terminal Half-Life (t ½) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | 17.5 days | Geometric Coefficient of Variation 54 |
Secondary
Time to Maximum Concentration (Tmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)
Blood samples were collected at specified intervals for the determination of Tmax. Tmax was defined as time to the maximum concentration of pembrolizumab reached. Tmax was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time frame: Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Population: All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available Tmax data. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose PK analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) | Time to Maximum Concentration (Tmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | 0.05 days |
| Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) | Time to Maximum Concentration (Tmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | 0.17 days |
| Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) | Time to Maximum Concentration (Tmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1) | 0.17 days |