Trial Outcomes & Findings for Study of Pembrolizumab Given With Ipilimumab or Placebo in Participants With Untreated Metastatic Non-Small Cell Lung Cancer (NSCLC) (MK-3475-598/KEYNOTE-598) (NCT NCT03302234)

Last Updated: 2023-09-26

Results Overview

OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of analysis were censored at the date of last known contact. The median survival (in months) and the associated 95% confidence intervals (CIs) were reported using Kaplan-Meier method was used. Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and predominant tumor history (squamous versus non-squamous) was used to estimate hazard ratio (HR) and 95% CIs for first course study treatment per protocol.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

568 participants

Primary outcome timeframe

Up to approximately 32 months (through data cut-off date: 01 Sep 2020)

Results posted on

2023-09-26

Participant Flow

Of 568 participants randomized to the study, 563 received at least one dose of study treatment (All Treated Population) and were evaluable for all safety analysis.

Participant milestones

Participant milestones
Measure	Pembrolizumab + Ipilimumab Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Overall Study STARTED	284	284
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	284	284

Reasons for withdrawal

Reasons for withdrawal
Measure	Pembrolizumab + Ipilimumab Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Overall Study Death	191	192
Overall Study Withdrawal by Subject	2	2
Overall Study Sponsor Decision	90	89
Overall Study Laryngeal carcinoma	0	1
Overall Study Not Reported	1	0

Baseline Characteristics

Study of Pembrolizumab Given With Ipilimumab or Placebo in Participants With Untreated Metastatic Non-Small Cell Lung Cancer (NSCLC) (MK-3475-598/KEYNOTE-598)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pembrolizumab + Ipilimumab n=284 Participants Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo n=284 Participants Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Total n=568 Participants Total of all reporting groups
Age, Continuous	63.7 Years STANDARD_DEVIATION 9.3 • n=5 Participants	64.5 Years STANDARD_DEVIATION 8.8 • n=7 Participants	64.1 Years STANDARD_DEVIATION 9.1 • n=5 Participants
Sex/Gender, Customized Male	202 Participants n=5 Participants	191 Participants n=7 Participants	393 Participants n=5 Participants
Sex/Gender, Customized Female	82 Participants n=5 Participants	92 Participants n=7 Participants	174 Participants n=5 Participants
Sex/Gender, Customized Undifferentiated	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	54 Participants n=5 Participants	37 Participants n=7 Participants	91 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	208 Participants n=5 Participants	225 Participants n=7 Participants	433 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	22 Participants n=5 Participants	22 Participants n=7 Participants	44 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) Asian	33 Participants n=5 Participants	31 Participants n=7 Participants	64 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	218 Participants n=5 Participants	223 Participants n=7 Participants	441 Participants n=5 Participants
Race (NIH/OMB) More than one race	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	22 Participants n=5 Participants	22 Participants n=7 Participants	44 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) performance status 0 = Fully active; no performance restrictions	101 Participants n=5 Participants	104 Participants n=7 Participants	205 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) performance status 1 = Strenuous physical activity restricted; fully ambulatory & able to carry out light work	183 Participants n=5 Participants	180 Participants n=7 Participants	363 Participants n=5 Participants
Tumor histology Squamous	77 Participants n=5 Participants	81 Participants n=7 Participants	158 Participants n=5 Participants
Tumor histology Non squamous	207 Participants n=5 Participants	203 Participants n=7 Participants	410 Participants n=5 Participants
Geographic region East Asia	32 Participants n=5 Participants	31 Participants n=7 Participants	63 Participants n=5 Participants
Geographic region Non-East Asia	252 Participants n=5 Participants	253 Participants n=7 Participants	505 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to approximately 32 months (through data cut-off date: 01 Sep 2020)

Population: All randomized participants

Outcome measures

Outcome measures
Measure	Pembrolizumab + Ipilimumab n=284 Participants Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo n=284 Participants Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Overall Survival (OS)	21.4 Months Interval 16.6 to NA = Upper limit OS was not reached at the time of last disease assessment due to insufficient number of participants with events.	21.9 Months Interval 18.0 to NA = Upper limit OS was not reached at the time of last disease assessment due to insufficient number of participants with events.

PRIMARY outcome

Timeframe: Up to approximately 32 months (through data cut-off date 01 Sep 2020)

Population: All randomized participants

PFS was defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 based on BICR or death due to any cause, whichever occurs first. PD is defined as ≥20% increase in sum of diameters of target lesions. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The median survival (in months) and associated 95% CIs were reported using Kaplan-Meier method. Cox regression model with Efron's method of tie handling with treatment as covariate stratified by ECOG performance status (0 vs. 1), geographic region of the enrolling site (East Asia vs. non-East Asia), and predominant tumor history (squamous vs. non-squamous) was used to estimate HR and 95% CIs for first course study treatment per protocol.

Outcome measures

Outcome measures
Measure	Pembrolizumab + Ipilimumab n=284 Participants Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo n=284 Participants Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on Blinded Independent Central Review (BICR)	8.2 Months Interval 6.0 to 10.5	8.4 Months Interval 6.3 to 10.5

SECONDARY outcome

Timeframe: Up to approximately 32 months (data cut-off date 01 Sep 2020)

Population: All randomized participants

ORR was defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 by BICR. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Per protocol the ORR was calculated using the Miettinen \& Nurminen method stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and predominant tumor history (squamous versus non-squamous) for the first course of study treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab + Ipilimumab n=284 Participants Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo n=284 Participants Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Objective Response Rate (ORR) Per RECIST 1.1 Based on BICR	45.4 Percentage of Participants Interval 39.5 to 51.4	45.4 Percentage of Participants Interval 39.5 to 51.4

SECONDARY outcome

Timeframe: Up to approximately 32 months (data cut-off date 01 Sep 2020)

Population: All randomized participants with confirmed complete response or partial response

For participants who demonstrated a confirmed CR (Disappearance of all target lesions) or confirmed 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 CR or PR until PD or death due to any cause, whichever occurs first. 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. RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data. Per protocol, the DOR for all participants who experienced a CR or PR was presented for the first course of study treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab + Ipilimumab n=129 Participants Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo n=129 Participants Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Duration of Response (DOR) Per RECIST 1.1 Based on BICR	16.1 Months Interval 12.7 to 26.0	17.3 Months Interval 14.8 to NA = DOR 95%CI upper limit not reached at the time of last disease assessment due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: Up to approximately 32 months (data cut-off date 01 Sep 2020)

Population: All participants randomized who received at least one dose of study treatment and had at least one EORTC QLQ-LC13 and EORTC QLQ-C30 available.

TTD was defined as the time to the first onset of a 10-point or greater score deterioration from baseline in any one of the 3 symptoms (cough, pain in chest or shortness of breath), confirmed by a second adjacent 10-point or greater score deterioration from baseline. Cough was based on EORTC QLQ-LC13 question 1, pain in chest was based on EORTC QLQ-LC13 question 10, and shortness of breath was based on EORTC QLQ-C30 question 8. Per protocol, TTD was reported for first course study treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab + Ipilimumab n=268 Participants Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo n=270 Participants Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Time to True Deterioration (TTD) in Cough, Pain in Chest, and Shortness of Breath	NA Months Interval 12.9778 to NA = Median TTD and upper limit for TTD was not reached at the time of last disease assessment due to insufficient number of participants with events.	20.0416 Months Interval 12.7149 to NA = Upper limit for TTD was not reached at the time of last disease assessment due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: Up to approximately 27 months

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

An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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. Per protocol, the number of participants who experienced an AE were reported for the first course of study treatment and follow up.

Outcome measures

Outcome measures
Measure	Pembrolizumab + Ipilimumab n=282 Participants Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo n=281 Participants Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Number of Participants Who Experienced an Adverse Event (AE)	272 Participants	263 Participants

SECONDARY outcome

Timeframe: Up to approximately 24 months

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

An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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. Per protocol, the number of participants who discontinued study treatment due to an AE were reported for the first course of study treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab + Ipilimumab n=282 Participants Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo n=281 Participants Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Number of Participants Who Discontinued Study Treatment Due to an AE	105 Participants	57 Participants

SECONDARY outcome

Timeframe: Baseline, Week 18

Population: All randomized participants who received at least one dose of study treatment and had at least one EORTC QLQ-C30 assessment available.

The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" were scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores were standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. Per protocol, the change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score were presented for first course study treatment.

Outcome measures

Outcome measures
Measure	Pembrolizumab + Ipilimumab n=279 Participants Participants received 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued ipilimumab and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).	Pembrolizumab + Placebo n=280 Participants Participants received 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. Per Amendment (AM) 6, (effective date: 11-Dec-2020), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\~2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \~1 year).
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Scale Score to Week 18	3.72 Score on a scale Interval 0.91 to 6.53	4.14 Score on a scale Interval 1.42 to 6.86

Adverse Events

Pembrolizumab+Ipilimumab (First Course)

Serious events: 146 serious events

Other events: 251 other events

Deaths: 191 deaths

Pembrolizumab+Placebo (First Course)

Serious events: 114 serious events

Other events: 232 other events

Deaths: 188 deaths

Pembrolizumab + Placebo (Second Course)

Serious events: 4 serious events

Other events: 10 other events

Deaths: 4 deaths

Serious adverse events

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