Study of Pembrolizumab (MK-3475) in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (P07990/MK-3475-001/KEYNOTE-001) (KEYNOTE-001)

• ClinicalTrials.gov Identifier: NCT01295827
• Recruitment Status: Completed
• First Posted: February 15, 2011
• Results First Posted: December 13, 2019
• Last Update Posted: December 13, 2019
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cancer, Solid Tumor	Biological: Pembrolizumab	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1260 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of Single Agent Pembrolizumab (MK-3475) in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma (KEYNOTE 001)
• Actual Study Start Date: March 4, 2011
• Actual Primary Completion Date: November 5, 2018
• Actual Study Completion Date: December 11, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A); During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab intravenous (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 every 2 weeks (Q2W) starting with Cycle 2.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: NSCLC: Pembrolizumab 2 mg/kg Q3W (Part E-Not Enrolled); Participants were to receive pembrolizumab IV at a dose of 2 mg/kg Q3W. No participants were enrolled in this arm.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: NSCLC: Pembrolizumab 5 mg/kg Q3W (Part E-Not Enrolled); Participants were to receive pembrolizumab IV at a dose of 5 mg/kg Q3W. No participants were enrolled in this arm.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®
Experimental: NSCLC: Pembrolizumab 10 mg/kg Q3W (Part E-Not Enrolled); Participants were to receive pembrolizumab IV at a dose of 10 mg/kg Q3W. No participants were enrolled in this arm.	Biological: Pembrolizumab; IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.; Other Names: MK-3475; KEYTRUDA®

Outcome Measures

Primary Outcome Measures :

1. 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) [ Time Frame: 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.
2. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: 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.
3. 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) [ Time Frame: 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).
4. ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F) [ Time Frame: 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 Outcome Measures :

1. ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D) [ Time Frame: 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).
2. ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) [ Time Frame: 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).
3. 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) [ 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) ]
   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.
4. Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (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) ]
   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.
5. Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (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) ]
   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.
6. Time to Maximum Concentration (Tmax) of Pembrolizumab in Solid Tumor Participants (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) ]
   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.
7. Terminal Half-Life (t ½) of Pembrolizumab in Solid Tumor Participants (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) ]
   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.
8. Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 21 (AUC 0-21) in Solid Tumor Participants (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) ]
   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.
9. Area Under the Concentration-Time Curve of Pembrolizumab From Day 21 to Day 42 (AUC21-42) in Solid Tumor Participants (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) ]
   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.
10. Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2) [ 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) ]
    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.
11. Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D) [ 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) ]
    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.
12. Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F) [ 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) ]
    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.
13. 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) [ Time Frame: 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).
14. 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) [ Time Frame: 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).
15. Disease Control Rate (DCR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D) [ Time Frame: 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).
16. Duration of Response (DOR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and 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) ]
    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).
17. Progression Free Survival (PFS) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B Plus D) [ Time Frame: 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).
18. Overall Survival (OS) in Melanoma Participants (Parts B Plus D) [ Time Frame: 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).
19. DCR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) [ Time Frame: 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).
20. DOR According to irRC as Assessed by Investigator in Melanoma Participants (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) ]
    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).
21. PFS According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D) [ Time Frame: 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).
22. DCR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) [ Time Frame: 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).
23. DOR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (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) ]
    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).
24. PFS According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F) [ Time Frame: 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).
25. OS in NSCLC Participants (Parts C Plus F) [ Time Frame: 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).
26. DCR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) [ Time Frame: 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).
27. DOR According to irRC as Assessed by Investigator in NSCLC Participants (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) ]
    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).
28. PFS According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F) [ Time Frame: 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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme LLC:

Study Protocol and Statistical Analysis Plan  [PDF] December 21, 2017

More Information

Publications of Results:

Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. doi: 10.1016/S0140-6736(14)60958-2. Epub 2014 Jul 15.

Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, Chen C, Smith L, Espino G, Gergich K, Delgado L, Daud A, Lindia JA, Li XN, Pierce RH, Yearley JH, Wu D, Laterza O, Lehnert M, Iannone R, Tolcher AW. Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors. Clin Cancer Res. 2015 Oct 1;21(19):4286-93. doi: 10.1158/1078-0432.CCR-14-2607. Epub 2015 May 14.

Chatterjee M, Turner DC, Felip E, Lena H, Cappuzzo F, Horn L, Garon EB, Hui R, Arkenau HT, Gubens MA, Hellmann MD, Dong D, Li C, Mayawala K, Freshwater T, Ahamadi M, Stone J, Lubiniecki GM, Zhang J, Im E, De Alwis DP, Kondic AG, Flotten O. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol. 2016 Jul;27(7):1291-8. doi: 10.1093/annonc/mdw174. Epub 2016 Apr 26.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.

Hamid O, Robert C, Daud A, Carlino MS, Mitchell TC, Hersey P, Schachter J, Long GV, Hodi FS, Wolchok JD, Arance A, Grob JJ, Joshua AM, Weber JS, Mortier L, Jensen E, Diede SJ, Moreno BH, Ribas A. Long-term outcomes in patients with advanced melanoma who had initial stable disease with pembrolizumab in KEYNOTE-001 and KEYNOTE-006. Eur J Cancer. 2021 Nov;157:391-402. doi: 10.1016/j.ejca.2021.08.013. Epub 2021 Sep 25.

Robert C, Hwu WJ, Hamid O, Ribas A, Weber JS, Daud AI, Hodi FS, Wolchok JD, Mitchell TC, Hersey P, Dronca R, Joseph RW, Boutros C, Min L, Long GV, Schachter J, Puzanov I, Dummer R, Lin J, Ibrahim N, Diede SJ, Carlino MS, Joshua AM. Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma. Eur J Cancer. 2021 Feb;144:182-191. doi: 10.1016/j.ejca.2020.11.010. Epub 2020 Dec 24.

Lala M, Li TR, de Alwis DP, Sinha V, Mayawala K, Yamamoto N, Siu LL, Chartash E, Aboshady H, Jain L. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020 May;131:68-75. doi: 10.1016/j.ejca.2020.02.016. Epub 2020 Apr 15. Erratum In: Eur J Cancer. 2021 Feb;144:400.

van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.

Garon EB, Hellmann MD, Rizvi NA, Carcereny E, Leighl NB, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, Patnaik A, Gubens M, Ramalingam SS, Felip E, Goldman JW, Scalzo C, Jensen E, Kush DA, Hui R. Five-Year Overall Survival for Patients With Advanced Non-Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J Clin Oncol. 2019 Oct 1;37(28):2518-2527. doi: 10.1200/JCO.19.00934. Epub 2019 Jun 2.

Leighl NB, Hellmann MD, Hui R, Carcereny E, Felip E, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, Patnaik A, Gubens M, Ramalingam SS, Lubiniecki GM, Zhang J, Piperdi B, Garon EB. Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study. Lancet Respir Med. 2019 Apr;7(4):347-357. doi: 10.1016/S2213-2600(18)30500-9. Epub 2019 Mar 12.

Wang M, Chen C, Jemielita T, Anderson J, Li XN, Hu C, Kang SP, Ibrahim N, Ebbinghaus S. Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma? J Immunother Cancer. 2019 Feb 8;7(1):39. doi: 10.1186/s40425-019-0513-4.

Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph R, Weber JS, Dronca R, Mitchell TC, Patnaik A, Zarour HM, Joshua AM, Zhao Q, Jensen E, Ahsan S, Ibrahim N, Ribas A. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019 Apr 1;30(4):582-588. doi: 10.1093/annonc/mdz011.

Hamid O, Robert C, Ribas A, Hodi FS, Walpole E, Daud A, Arance AS, Brown E, Hoeller C, Mortier L, Schachter J, Long J, Ebbinghaus S, Ibrahim N, Butler M. Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006. Br J Cancer. 2018 Sep;119(6):670-674. doi: 10.1038/s41416-018-0207-6. Epub 2018 Sep 11.

Joseph RW, Elassaiss-Schaap J, Kefford R, Hwu WJ, Wolchok JD, Joshua AM, Ribas A, Hodi FS, Hamid O, Robert C, Daud A, Dronca R, Hersey P, Weber JS, Patnaik A, de Alwis DP, Perrone A, Zhang J, Kang SP, Ebbinghaus S, Anderson KM, Gangadhar TC. Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients with Melanoma Treated with Pembrolizumab. Clin Cancer Res. 2018 Oct 15;24(20):4960-4967. doi: 10.1158/1078-0432.CCR-17-2386. Epub 2018 Apr 23. Erratum In: Clin Cancer Res. 2018 Dec 1;24(23):6098.

Brogden KA, Parashar D, Hallier AR, Braun T, Qian F, Rizvi NA, Bossler AD, Milhem MM, Chan TA, Abbasi T, Vali S. Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy. BMC Cancer. 2018 Feb 27;18(1):225. doi: 10.1186/s12885-018-4134-y. Erratum In: BMC Cancer. 2018 Apr 12;18(1):413.

Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM, Hwu WJ, Weber JS, Gangadhar TC, Joseph RW, Dronca R, Patnaik A, Zarour H, Kefford R, Hersey P, Zhang J, Anderson J, Diede SJ, Ebbinghaus S, Hodi FS. Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. J Clin Oncol. 2018 Jun 10;36(17):1668-1674. doi: 10.1200/JCO.2017.75.6270. Epub 2017 Dec 28.

Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon EB, Lee P. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017 Jul;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7. Epub 2017 May 24. Erratum In: Lancet Oncol. 2017 Jul;18(7):e371.

Hui R, Garon EB, Goldman JW, Leighl NB, Hellmann MD, Patnaik A, Gandhi L, Eder JP, Ahn MJ, Horn L, Felip E, Carcereny E, Rangwala R, Lubiniecki GM, Zhang J, Emancipator K, Roach C, Rizvi NA. Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial. Ann Oncol. 2017 Apr 1;28(4):874-881. doi: 10.1093/annonc/mdx008.

Daud AI, Wolchok JD, Robert C, Hwu WJ, Weber JS, Ribas A, Hodi FS, Joshua AM, Kefford R, Hersey P, Joseph R, Gangadhar TC, Dronca R, Patnaik A, Zarour H, Roach C, Toland G, Lunceford JK, Li XN, Emancipator K, Dolled-Filhart M, Kang SP, Ebbinghaus S, Hamid O. Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. J Clin Oncol. 2016 Dec;34(34):4102-4109. doi: 10.1200/JCO.2016.67.2477. Epub 2016 Oct 31.

Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C. Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. JAMA. 2016 Apr 19;315(15):1600-9. doi: 10.1001/jama.2016.4059. Erratum In: JAMA. 2016 Jun 14;315(22):2472.

Hodi FS, Hwu WJ, Kefford R, Weber JS, Daud A, Hamid O, Patnaik A, Ribas A, Robert C, Gangadhar TC, Joshua AM, Hersey P, Dronca R, Joseph R, Hille D, Xue D, Li XN, Kang SP, Ebbinghaus S, Perrone A, Wolchok JD. Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. J Clin Oncol. 2016 May 1;34(13):1510-7. doi: 10.1200/JCO.2015.64.0391. Epub 2016 Mar 7.

Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. doi: 10.1056/NEJMoa1501824. Epub 2015 Apr 19.

Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. doi: 10.1056/NEJMoa1305133. Epub 2013 Jun 2. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01295827
• Other Study ID Numbers: P07990; MK-3475-001 ( Other Identifier: Merck Protocol Number ); 2011-002371-42 ( EudraCT Number ); P07990 ( Other Identifier: Merck ); KEYNOTE-001 ( Other Identifier: Merck )
• First Posted: February 15, 2011
• Results First Posted: December 13, 2019
• Last Update Posted: December 13, 2019
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme LLC:

Melanoma; Carcinoma; Cancer; Advanced cancer; Metastatic cancer; Metastatic melanoma; Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1)

Additional relevant MeSH terms:

Carcinoma; Melanoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action