Trial Outcomes & Findings for Study of the Safety, Tolerability, Pharmacokinetics and Efficacy of Pembrolizumab (MK-3475) in Chinese Participants With Non-Small-Cell Lung Cancer (MK-3475-032/KEYNOTE-032) (NCT NCT02835690)

Last Updated: 2022-10-26

Results Overview

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to be a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who experienced at least one AE was reported per protocol for the first course of treatment.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

44 participants

Primary outcome timeframe

Up to ~13 months (through Final Analysis database cut-off date of 19-Sept-2017)

Results posted on

2022-10-26

Participant Flow

Of 44 participants randomized, 42 received treatment. Per protocol, response/progression or adverse events (AEs) that occurred during the second course were not counted towards efficacy outcome measures or safety outcome measures, respectively.

Participant milestones

Participant milestones
Measure	Pembrolizumab 2 mg/kg Participants received pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Pembrolizumab 10 mg/kg Participants received pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Pembrolizumab 200 mg Fixed Dose Participants received pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
Overall Study STARTED	14	15	15
Overall Study Received First Course of Pembrolizumab	14	13	15
Overall Study Received Second Course of Pembrolizumab	1	0	0
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	14	15	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Pembrolizumab 2 mg/kg Participants received pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Pembrolizumab 10 mg/kg Participants received pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Pembrolizumab 200 mg Fixed Dose Participants received pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
Overall Study Death	12	11	13
Overall Study Transferred to Extension Study	2	2	1
Overall Study Did Not Continue on Extension Study	0	0	1
Overall Study Not Treated	0	2	0

Baseline Characteristics

Study of the Safety, Tolerability, Pharmacokinetics and Efficacy of Pembrolizumab (MK-3475) in Chinese Participants With Non-Small-Cell Lung Cancer (MK-3475-032/KEYNOTE-032)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants received pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Pembrolizumab 10 mg/kg n=13 Participants Participants received pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants received pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Total n=42 Participants Total of all reporting groups
Age, Continuous	53.2 years STANDARD_DEVIATION 9.5 • n=5 Participants	56.2 years STANDARD_DEVIATION 11.5 • n=7 Participants	56.7 years STANDARD_DEVIATION 8.8 • n=5 Participants	55.4 years STANDARD_DEVIATION 9.8 • n=4 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants	15 Participants n=4 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	9 Participants n=7 Participants	9 Participants n=5 Participants	27 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=5 Participants	13 Participants n=7 Participants	15 Participants n=5 Participants	42 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized Chinese	14 Participants n=5 Participants	13 Participants n=7 Participants	15 Participants n=5 Participants	42 Participants n=4 Participants

PRIMARY outcome

Timeframe: Up to ~13 months (through Final Analysis database cut-off date of 19-Sept-2017)

Population: All randomized participants that received at least one dose of study treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Number of Participants Who Experienced an Adverse Event (AE)	14 Participants	13 Participants	14 Participants

PRIMARY outcome

Timeframe: Up to ~12 months (through Final Analysis database cut-off date of 19-Sept-2017)

Population: All randomized participants that received at least one dose of study treatment.

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to be a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who discontinued study treatment due to an AE was reported per protocol for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Number of Participants Who Discontinued Study Drug Due to an AE	0 Participants	1 Participants	3 Participants

PRIMARY outcome

Timeframe: Cycle 1 Day 1: pre-dose [-1 to 0 hour] and post-dose at 0 [up to 0.5], 6 [±0.5], 24, 48, 168, 336, and 504 [±2 for 24 to 504] hours after completion of pembrolizumab infusion. Cycle 1= 28 days

Population: All randomized participants who received a pembrolizumab dose, with available pharmacokinetic (PK) data, and who did not have any protocol deviation interfering with PK.

AUC was defined as a measure of pembrolizumab exposure that was calculated as the product of plasma drug concentration and time. Blood samples were collected pre-dose and post-dose at multiple time points up to 28 days during cycle 1 to estimate AUC(0-28 days) following single dose administration for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Single Dose PK: Area Under the Plasma Concentration Curve From 0-28 Days (AUC[0-28 Days]) of Pembrolizumab	437.10 μg•day/mL Interval 388.94 to 491.22	1979.62 μg•day/mL Interval 1737.75 to 2255.15	637.22 μg•day/mL Interval 569.89 to 712.51

PRIMARY outcome

Population: All randomized participants who received a pembrolizumab dose, with available PK data, and who did not have any protocol deviation interfering with PK.

Cmax was defined as the maximum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected pre-dose and post-dose at multiple time points up to 28 days during cycle 1 to estimate Cmax following single dose administration for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Single-Dose PK: Maximum Plasma Concentration (Cmax) of Pembrolizumab	50.62 μg/mL Interval 42.34 to 60.52	213.12 μg/mL Interval 191.45 to 237.25	76.21 μg/mL Interval 63.59 to 91.32

PRIMARY outcome

Population: All randomized participants who received a pembrolizumab dose, with available PK data, and who did not have any protocol deviation interfering with PK.

Tmax was defined as the time required post dosing to reach a maximum plasma concentration of pembrolizumab. Blood samples were collected pre-dose and post-dose at multiple time points up to 28 days at cycle 1 to estimate Tmax following single dose administration for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Single Dose PK: Time to Cmax (Tmax) of Pembrolizumab	0.06 day Interval 0.03 to 2.02	0.05 day Interval 0.02 to 0.27	0.04 day Interval 0.02 to 0.27

PRIMARY outcome

Population: All randomized participants who received a pembrolizumab dose, with available PK data, and who did not have any protocol deviation interfering with PK.

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. Blood samples were collected pre-dose and post-dose at multiple time points up to 28 days at cycle 1 to estimate t½ following single dose administration for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Single Dose PK: Apparent Terminal Half-Life (t1/2) of Pembrolizumab	14.10 Day Interval 9.56 to 31.6	16.00 Day Interval 10.5 to 23.8	12.70 Day Interval 4.15 to 24.5

PRIMARY outcome

Timeframe: Cycle 8 Day 1: pre-dose [-1 to 0 hour]. (Cycle 1 = 28 days, Cycles 2-8 = 21 days).

Population: All randomized participants who received a pembrolizumab dose, had available Ctrough data, and who did not have any protocol deviation interfering with PK.

Ctrough was defined as the minimum concentration that occurred immediately prior to the administration of pembrolizumab in Cycle 8. Blood samples were collected pre-dose at Cycle 8 to estimate Ctrough following multiple dose administrations of pembrolizumab for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=8 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=5 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=5 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Multiple Dose PK: Trough Plasma Concentration (Ctrough) of Pembrolizumab	21.53 μg/mL Interval 15.76 to 29.41	78.35 μg/mL Interval 56.09 to 109.45	25.46 μg/mL Interval 17.7 to 36.63

PRIMARY outcome

Timeframe: Cycle 8 Day 1: pre-dose [-1 to 0 hour] and post-dose at 0 [up to 0.5], 6 [up to 0.5], 24, 48, 168, 336, and 504 [±2 for 24 to 504] hours after completion of pembrolizumab infusion. Cycle 8 up to 175 days (Cycle 1 = 28 days, Cycles 2-8 = 21 days).

Population: All randomized participants who received a pembrolizumab dose, had available AUC(0-21 days) data, and who did not have any protocol deviation interfering with PK.

AUC was defined as a measure of pembrolizumab exposure that was calculated as the product of plasma drug concentration and time at steady state following multiple doses. Blood samples were collected pre-dose and post-dose at multiple time points up to 21 days during cycle 8 to assess AUC(0-21 days) at steady state for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=7 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=5 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=4 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Multiple Dose PK: AUC(0-21 Days) of Pembrolizumab at Steady State	730.94 μg•day/mL Interval 627.38 to 851.6	2819.19 μg•day/mL Interval 2009.36 to 3955.43	930.99 μg•day/mL Interval 724.37 to 1196.56

PRIMARY outcome

Population: All randomized participants who received a pembrolizumab dose, had available Cmax data, and who did not have any protocol deviation interfering with PK.

Cmax was defined as the maximum concentration of pembrolizumab observed in plasma at steady state following multiple doses. Blood samples were collected pre-dose and post-dose at multiple time points up to 21 days during cycle 8 to assess Cmax assessment at steady state for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=8 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=5 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=5 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Multiple Dose PK: Cmax of Pembrolizumab at Steady State	66.67 g/mL Interval 56.9 to 78.1	268.59 g/mL Interval 217.81 to 331.21	92.22 g/mL Interval 81.66 to 104.16

SECONDARY outcome

Timeframe: Up to ~13 months (through Final Analysis database cut-off date of 19-Sept-2017)

Population: All randomized participants that received at least one dose of study treatment and with measurable disease at baseline as assessed by central radiology review.

ORR was defined as the percentage of participants who had a Complete Response (CR: disappearance of all lesions) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions, without evidence of progression based on non-target or new lesions) as assessed by central radiologists' review per RECIST 1.1 which is 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 per RECIST 1.1 as assessed by central radiologists' review was reported for each arm per protocol for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by Central Radiologists' Review	0.0 Percentage of participants Interval 0.0 to 23.2	23.1 Percentage of participants Interval 5.0 to 53.8	20.0 Percentage of participants Interval 4.3 to 48.1

SECONDARY outcome

Timeframe: Up to ~13 months (through Final Analysis database cut-off date of 19-Sept-2017)

Population: All randomized participants that received at least one dose of study treatment and with measurable disease at baseline as assessed by central radiology review.

ORR was defined as the percentage of participants who had confirmed responses assessed using RECIST 1.1 before PD or an immune-related Complete Response (irCR: Disappearance of all target lesions and non-target) or an immune-related Partial Response (irPR: At least a 30% decrease in the sum of diameters of target lesions, stability of non-target lesions no new lesions) after a single PD per irRECIST as assessed by central radiologists' review. Per RECIST 1.1, CR or PR was confirmed by repeated radiographic assessment no less than 4 weeks from the first documented response. If site-assessed PD was verified by the central imaging vendor, the site could elect to continue treatment, repeat imaging ≥4 weeks later and assess tumor response or confirmed progression per irRECIST. The percentage of participants who experienced a CR or PR per RECIST 1.1 or irCR or irPR per irRECIST as assessed by central radiologists' review was reported for each arm per protocol for first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
ORR Per Immune-related RECIST (irRECIST) as Assessed by Central Radiologists' Review	0.0 Percentage of participants Interval 0.0 to 23.2	23.1 Percentage of participants Interval 5.0 to 53.8	20.0 Percentage of participants Interval 4.3 to 48.1

SECONDARY outcome

Timeframe: Up to ~13 months (through Final Analysis database cut-off date of 19-Sept-2017)

Population: All randomized participants that received at least one dose of study treatment, had measurable disease at baseline as assessed by central radiology review, and who demonstrated a confirmed response (CR or PR). No participants in the Pembrolizumab 2 mg/kg group were eligible for this analysis.

For participants who demonstrated a confirmed CR (disappearance of all lesions) or confirmed PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by central radiologists' review, DOR was defined as the time from first documented evidence of a CR or PR until disease progression or death. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The DOR per RECIST 1.1 as assessed by central radiologists' review for all participants who experienced a confirmed CR or PR was reported for each arm per protocol for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=3 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=3 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Duration of Response (DOR) Per RECIST 1.1 as Assessed by Central Radiologists' Review	—	6.28 Months Interval 2.0 to 6.28	4.1 Months Interval 2.0 to 4.11

SECONDARY outcome

Timeframe: Up to ~13 months (through Final Analysis database cut-off date of 19-Sept-2017)

Population: All randomized participants that received at least one dose of study treatment, had measurable disease at baseline as assessed by central radiology review, and who demonstrated a confirmed response (iCR or iPR). No participants in the Pembrolizumab 2 mg/kg group were eligible for this analysis.

For participants who demonstrated confirmed CR (disappearance of all target lesions and non-target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 or CR or PR after a single PD, DOR was defined as the time from the first documented CR or PR, or irCR or irPR, until an immune-related progressive disease (irPD) or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Per irRECIST, irPD was defined as after a single PD, ≥20% increase in the sum of diameters of target lesions, or unequivocal worsening of non-target lesions or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. DOR per irRECIST assessed by central radiologists' review for all participants with confirmed CR or PR or irCR or irPR was reported for each arm per protocol for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=3 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=3 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
DOR Per irRECIST as Assessed by Central Radiologists' Review	—	NA Months NA=The median of DOR and the lower and upper ranges of DOR were not reached (no progressive disease by time of last disease assessment).	NA Months NA=The median of DOR and the lower and upper ranges of DOR were not reached (no progressive disease by time of last disease assessment).

SECONDARY outcome

Timeframe: Up to ~13 months (through Final Analysis database cut-off date of 19-Sept-2017)

Population: All randomized participants that received at least one dose of study treatment.

PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as either a 20% increase from nadir in target lesions, unequivocal progression of nontarget lesions, or the appearance of new lesions. PFS per RECIST 1.1 as assessed by central radiologists' review was reported for each arm per protocol for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Central Radiologists' Review	2.1 Months Interval 2.0 to 4.2	2.7 Months Interval 2.1 to 8.2	2.1 Months Interval 1.3 to 6.4

SECONDARY outcome

Timeframe: Up to ~13 months (through Final Analysis database cut-off date of 19-Sept-2017)

Population: All randomized participants that received at least one dose of study treatment.

PFS was defined as the time from randomization to the first documented immune-based confirmed progressive disease (iCPD) or death due to any cause, whichever occurred first. Per iRECIST, iCPD is defined as worsening of any existing cause of progression, or the appearance of any other cause of progression, relative to the initial appearance of progressive disease by RECIST 1.1. PFS per irRECIST as assessed by central radiologists' review is reported for each arm per protocol for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
PFS Per irRECIST as Assessed by Central Radiologists' Review	2.2 Months Interval 2.0 to 4.4	6.2 Months Interval 2.1 to NA=The upper limit of the PFS 95% confidence interval (CI) was not reached by the time of the 19-Sept-2017 data cut-off.	6.4 Months Interval 1.3 to NA=The upper limit of the PFS 95% confidence interval (CI) was not reached by the time of the 19-Sept-2017 data cut-off.

SECONDARY outcome

Timeframe: Up to ~13 months (through Final Analysis database cut-off date of 19-Sept-2017)

Population: All randomized participants that received at least one dose of study treatment.

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 censored at the date of the last follow-up. OS was reported for each arm using a 19-Sept-2017 data cut-off date per protocol for the first course of treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab 2 mg/kg n=14 Participants Participants receive pembrolizumab 2 mg/kg administered intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 10 mg/kg n=13 Participants Participants receive pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.	Pembrolizumab 200 mg Fixed Dose n=15 Participants Participants receive pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 is 28 days and subsequent cycles are 21 days.
Overall Survival (OS)	NA Months Interval 4.4 to NA=The median of OS and the upper limit of the OS 95% CI were not reached by the time of the 19-Sept-2017 data cut-off.	9.4 Months Interval 6.2 to NA=The upper limit of the OS 95% CI was not reached by the time of the 19-Sept-2017 data cut-off.	NA Months Interval 1.3 to NA=The median of OS and the upper limit of the OS 95% CI were not reached by the time of the 19-Sept-2017 data cut-off.

Adverse Events

Pembrolizumab 2 mg/kg First Course

Serious events: 2 serious events

Other events: 14 other events

Deaths: 11 deaths

Pembrolizumab 10 mg/kg First Course

Serious events: 1 serious events

Other events: 13 other events

Deaths: 12 deaths

Pembrolizumab 200 mg Fixed Dose First Course

Serious events: 3 serious events

Other events: 14 other events

Deaths: 13 deaths

Pembrolizumab 2 mg/kg Second Course

Serious events: 0 serious events

Other events: 0 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Pembrolizumab 2 mg/kg First Course n=14 participants at risk Participants received pembrolizumab 2 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days	Pembrolizumab 10 mg/kg First Course n=13 participants at risk Participants received pembrolizumab 10 mg/kg administered IV Q3W for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days.	Pembrolizumab 200 mg Fixed Dose First Course n=15 participants at risk Participants received pembrolizumab 200 mg fixed dose administered IV Q3W for up to 35 administrations. Cycle 1 was 28 days and subsequent cycles were 21 days.	Pembrolizumab 2 mg/kg Second Course n=1 participants at risk Eligible participants who stopped the initial course of pembrolizumab (2 mg/kg administered IV Q3W for up to 35 administrations) with Stable Disease (SD) or better but progressed after discontinuation initiated a second course of pembrolizumab at the same dose per the investigator's discretion for up to 17 cycles (up to approximately 1 additional year).
Eye disorders Eyelid ptosis	0.00% 0/14 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/13 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	6.7% 1/15 • Number of events 1 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/1 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/14 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	7.7% 1/13 • Number of events 1 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/15 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/1 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.
Infections and infestations Pneumonia	14.3% 2/14 • Number of events 2 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/13 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/15 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/1 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.
Nervous system disorders Cerebral infarction	0.00% 0/14 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/13 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	6.7% 1/15 • Number of events 1 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/1 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.
Skin and subcutaneous tissue disorders Dermatitis acneiform	0.00% 0/14 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/13 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	6.7% 1/15 • Number of events 1 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.	0.00% 0/1 • Up to ~65 months (through End of Trial database cut-off date of 31-Dec-2021) All-Cause Mortality was reported according to treatment course for all randomized participants. Serious and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme LLC

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.
Publication restrictions are in place

Restriction type: OTHER