Study of Pemetrexed+Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Participants With First Line Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-3475-189/KEYNOTE-189)-Japan Extension Study

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03950674
• Collaborator: (none)
• Enrollment: 40
• Locations: 10
• Arms: 2
• Anticipated Duration (Months): 83.5
• Patients Per Site: 4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a Japan Extension Study of Global Study MK-3475-189 (NCT02578680). This is an efficacy and safety study of pembrolizumab (MK-3475) combined with pemetrexed/platinum chemotherapy versus pemetrexed/platinum chemotherapy alone in adult Japanese participants with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have not previously received systemic therapy for advanced disease. Participants will be randomly assigned to receive pembrolizumab combined with pemetrexed/platinum (Investigators choice of cisplatin or carboplatin), OR pemetrexed/platinum (Investigators choice of cisplatin or carboplatin).

With Amendment 11 (effective date 31-Jan-2022), once the study objectives have been met or the study has ended, participants will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment.

The primary hypothesis is that pembrolizumab in combination with pemetrexed/platinum chemotherapy prolongs Progression-Free Survival (PFS) and Overall Survival (OS) compared to pemetrexed/platinum chemotherapy alone.

Condition or Disease	Intervention/Treatment	Phase
Non-Small-Cell Lung Carcinoma	Biological: Pembrolizumab 200 mg; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Dietary Supplement: Folic acid 350-1000 μg; Dietary Supplement: Vitamin B12 1000 μg; Drug: Dexamethasone 4 mg; Drug: Saline solution	Phase 3

Detailed Description

The MK-3475-189-Japan Extension Study will be identical to the global study (e.g. inclusion and exclusion criteria, study primary and secondary outcome measures and study procedures).

The MK-3475-189-Japanese Extension Study enrolled a total of 30 participants and the analyses included 10 participants (pembrolizumab =4; control = 6) that had been previously enrolled in the MK-3475-189 global study (NCT02578680), resulting in a total of 40 participants.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Phase III Study of Platinum+Pemetrexed Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Non-squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-189)
• Actual Study Start Date: Feb 22, 2016
• Actual Primary Completion Date: May 20, 2019
• Anticipated Study Completion Date: Feb 8, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab Participants receive pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression (up to 35 treatment administrations; up to approximately 2 years).	Biological: Pembrolizumab 200 mg; IV infusion; Drug: Cisplatin; IV infusion; Drug: Carboplatin; IV infusion; Drug: Pemetrexed; IV infusion; Dietary Supplement: Folic acid 350-1000 μg; Orally; at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed.; Dietary Supplement: Vitamin B12 1000 μg; Intramuscular injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration.; Drug: Dexamethasone 4 mg; For prophylaxis; orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.
Active Comparator: Control Participants receive saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurs, participants may be able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression (up to 35 treatment administrations; up to approximately 2 years).	Drug: Cisplatin; IV infusion; Drug: Carboplatin; IV infusion; Drug: Pemetrexed; IV infusion; Dietary Supplement: Folic acid 350-1000 μg; Orally; at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed.; Dietary Supplement: Vitamin B12 1000 μg; Intramuscular injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration.; Drug: Dexamethasone 4 mg; For prophylaxis; orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.; Drug: Saline solution; IV infusion

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging [Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)]

   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 ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 is presented.

2. Overall Survival (OS) [Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)]

   OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The OS is presented.

Secondary Outcome Measures

1. Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging [Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)]

   ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The percentage of participants who experienced a CR or PR is presented.

2. Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging [From time of first documented evidence of CR or PR through database cutoff date of 20-May-2019 (Up to approximately 31.2 months)]

   For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of 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 ≥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. Note: The appearance of one or more new lesions was also considered PD. DOR assessments were based on blinded central imaging review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented.

3. Number of Participants Who Experienced an Adverse Event (AE) [Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)]

   An AE was defined as any untoward medical occurrence in a study participant administered study drug and which does not necessarily have to have a causal relationship with this study drug. The number of participants who experienced an AE is presented.

4. Number of Participants Who Discontinued Any Study Drug Due to an AE [Up to approximately 24 months]

   The number of participants who discontinued any randomized study drug due to an AE is presented.

Other Outcome Measures

1. Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria [Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)]

   PFS was defined as the time from randomization to the first documented immune-related progressive disease (irPD) or death due to any cause, whichever occurred first. Per irRECIST, irPD was confirmed if any of the following are observed in 2 scans performed at least 4 weeks apart: target lesion sum of diameters remains ≥20 % and at least 5 mm absolute increase compared to nadir; non-target disease resulting in initial PD is qualitatively worse; new lesion resulting in initial irPD is qualitatively worse; additional new lesion(s) since last evaluation; or additional new non-target lesion progression since last evaluation. The PFS per irRECIST 1.1 is presented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Has a histologically-confirmed or cytologically confirmed diagnosis of stage IV nonsquamous NSCLC.

• Has confirmation that epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-directed therapy is not indicated.

• Has measurable disease.

• Has not received prior systemic treatment for their advanced/metastatic NSCLC.

• Can provide tumor tissue.

• Has a life expectancy of at least 3 months.

• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.

• Has adequate organ function

• If female of childbearing potential, is willing to use adequate contraception for the course of the study through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.

• If male with a female partner(s) of child-bearing potential, must agree to use adequate contraception starting with the first dose of study medication through 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.

Exclusion Criteria:

• Has predominantly squamous cell histology NSCLC.

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab.

• Before the first dose of study medication: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease, b) Has received antineoplastic biological therapy (e.g. erlotinib, crizotinib, cetuximab), c) Had major surgery (<3 weeks prior to first dose)

• Received radiation therapy to the lung that is >30 Gray (Gy) within 6 months of the first dose of study medication.

• Completed palliative radiotherapy within 7 days of the first dose of study medication.

• Is expected to require any other form of antineoplastic therapy while on study.

• Received a live-virus vaccination within 30 days of planned start of study medication.

• Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, peritoneal carcinomatosis.

• Known history of prior malignancy except if participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy, except for successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

• Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).

• Known sensitivity to any component of cisplatin, carboplatin or pemetrexed.

• Has active autoimmune disease that has required systemic treatment in past 2 years.

• Is on chronic systemic steroids.

• Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).

• Is unable or unwilling to take folic acid or vitamin B12 supplementation.

• Had prior treatment with any other anti-programmed cell death-1 (PD-1), or PD-ligand 1 (PD-L1) or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms. Has participated in any other pembrolizumab study and has been treated with pembrolizumab.

• Has an active infection requiring therapy.

• Has known history of Human Immunodeficiency Virus (HIV).

• Has known active Hepatitis B or C.

• Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.

• Is a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).

• Has symptomatic ascites or pleural effusion.

• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Hospital Organization Nagoya Medical Center ( Site 0324)	Nagoya	Aichi	Japan	460-0001
2	Kurume University Hospital ( Site 0326)	Kurume	Fukuoka	Japan	830-0011
3	Hyogo Cancer Center ( Site 0325)	Akashi	Hyogo	Japan	673-8558
4	Kanazawa University Hospital ( Site 0328)	Kanazawa	Ishikawa	Japan	920-8641
5	Kansai Medical University Hospital ( Site 0313)	Hirakata	Osaka	Japan	573-1191
6	Shizuoka Cancer Center Hospital and Research Institute ( Site 0322)	Sunto-gun	Shizuoka	Japan	411-8777
7	National Hospital Organization Shikoku Cancer Center ( Site 0303)	Matsuyama		Japan	791-0280
8	Okayama University Hospital ( Site 0327)	Okayama		Japan	700-8558
9	National Cancer Center Hospital ( Site 0301)	Tokyo		Japan	104-0045
10	The Cancer Institute Hospital of JFCR ( Site 0323)	Tokyo		Japan	135-8550

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Nov 6, 2017
• Statistical Analysis Plan - Nov 16, 2017

More Information

Additional Information:

• Merck Oncology Clinical Trials Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03950674
• Other Study ID Numbers: 3475-189 Japan Extension; 163421; MK-3475-189; KEYNOTE-189
• First Posted: May 15, 2019
• Last Update Posted: Aug 17, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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: Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1); Non-Small-Cell Lung Cancer (NSCLC); PD1; PD-1; PDL1; PD-L1; Non-Small-Cell Lung Cancer
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Folic Acid; Vitamin B 12; Hydroxocobalamin; Dexamethasone; Carboplatin; Pembrolizumab; Pemetrexed

Study Results

Participant Flow

Recruitment Details	The MK-3475-189-Japanese Extension Study enrolled a total of 30 participants and the analyses included 10 participants (pembrolizumab =4; control = 6) that had been previously enrolled in the MK-3475-189 global study (NCT02578680), resulting in a total of 40 participants.
Pre-assignment Detail	These results are based on a database cutoff date of 20-May-2019, at which time 30 participants were ongoing in the study. Four participants randomized to receive Control treatment had switched over to receive pembrolizumab monotherapy treatment. These results are for randomized treatment only.

Arm/Group Title	Pembrolizumab	Control
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Period Title: Overall Study
STARTED	25	15
Treated	25	15
Switched to Pembrolizumab	0	4
COMPLETED	0	0
NOT COMPLETED	25	15

Baseline Characteristics

Arm/Group Title	Pembrolizumab	Control	Total
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.	Total of all reporting groups
Overall Participants	25	15	40
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.6 (12.7)	60.9 (11.8)	60.1 (12.2)
Sex: Female, Male (Count of Participants)
Female	6 24%	3 20%	9 22.5%
Male	19 76%	12 80%	31 77.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	25 100%	15 100%	40 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	25 100%	15 100%	40 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Programmed Cell Death-Ligand 1 (PD-L1) Tumor Status (Count of Participants)
TPS <1%	14 56%	6 40%	20 50%
TPS ≥1%	10 40%	6 40%	16 40%
Not Evaluable	1 4%	3 20%	4 10%
Platinum Chemotherapy (Count of Participants)
Cisplatin	18 72%	8 53.3%	26 65%
Carboplatin	7 28%	7 46.7%	14 35%
Smoking Status (Count of Participants)
Never Smoker	7 28%	3 20%	10 25%
Former/Current Smoker	18 72%	12 80%	30 75%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Blinded Central Imaging
Description	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 ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 is presented.
Time Frame	Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants.

Arm/Group Title	Pembrolizumab	Control
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Measure Participants	25	15
Median (95% Confidence Interval) [Months]	16.5	7.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.12511
	Comments	One-sided p-value based on unstratified log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.27 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox regression model with treatment as a covariate stratified by PD-L1 status (≥1% vs. <1%), platinum chemotherapy (cisplatin vs. carboplatin) & smoking status (never vs. former/current). Pembrolizumab=numerator; Control=denominator.

2. Primary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The OS is presented.
Time Frame	Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants.

Arm/Group Title	Pembrolizumab	Control
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Measure Participants	25	15
Median (95% Confidence Interval) [Months]	NA	25.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03127
	Comments	One-sided p-value based on unstratified log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; 0.07 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox regression model with treatment as a covariate stratified by PD-L1 status (≥1% vs. <1%), platinum chemotherapy (cisplatin vs. carboplatin) & smoking status (never vs. former/current). Pembrolizumab=numerator; Control=denominator.

3. Secondary Outcome

Title	Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging
Description	ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The percentage of participants who experienced a CR or PR is presented.
Time Frame	Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants.

Arm/Group Title	Pembrolizumab	Control
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Measure Participants	25	15
Number (95% Confidence Interval) [Percentage of Participants]	56.0 224%	33.3 222%

4. Secondary Outcome

Title	Duration of Response (DOR) Per RECIST 1.1 as Assessed by Blinded Central Imaging
Description	For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of 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 ≥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. Note: The appearance of one or more new lesions was also considered PD. DOR assessments were based on blinded central imaging review with confirmation. The DOR per RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented.
Time Frame	From time of first documented evidence of CR or PR through database cutoff date of 20-May-2019 (Up to approximately 31.2 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who experienced a confirmed CR or confirmed PR.

Arm/Group Title	Pembrolizumab	Control
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Measure Participants	14	5
Median (95% Confidence Interval) [Months]	13.6	9.7

5. Secondary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a study participant administered study drug and which does not necessarily have to have a causal relationship with this study drug. The number of participants who experienced an AE is presented.
Time Frame	Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received ≥1 dose of study drug.

Arm/Group Title	Pembrolizumab	Control
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Measure Participants	25	15
Count of Participants [Participants]	25 100%	15 100%

6. Secondary Outcome

Title	Number of Participants Who Discontinued Any Study Drug Due to an AE
Description	The number of participants who discontinued any randomized study drug due to an AE is presented.
Time Frame	Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received ≥1 dose of study drug.

Arm/Group Title	Pembrolizumab	Control
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Measure Participants	25	15
Count of Participants [Participants]	9 36%	3 20%

7. Other Pre-specified Outcome

Title	Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria
Description	PFS was defined as the time from randomization to the first documented immune-related progressive disease (irPD) or death due to any cause, whichever occurred first. Per irRECIST, irPD was confirmed if any of the following are observed in 2 scans performed at least 4 weeks apart: target lesion sum of diameters remains ≥20 % and at least 5 mm absolute increase compared to nadir; non-target disease resulting in initial PD is qualitatively worse; new lesion resulting in initial irPD is qualitatively worse; additional new lesion(s) since last evaluation; or additional new non-target lesion progression since last evaluation. The PFS per irRECIST 1.1 is presented.
Time Frame	Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants.

Arm/Group Title	Pembrolizumab	Control
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.	Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.
Measure Participants	25	15
Median (95% Confidence Interval) [Months]	13.7	7.6

Adverse Events

Time Frame	Through Database Cutoff Date of 20-May-2019 (Up to approximately 31.2 months); Serious AEs: Up to 90 days after last dose of study drug, Other AEs: Up to 30 days after last dose of study drug
Adverse Event Reporting Description	Population: All participants receiving ≥1 dose of randomized study drug. Per protocol, progression of cancer under study was not considered an AE unless related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" & "Disease progression" not related to study drug are excluded as AEs. Four participants randomized to receive control and switched to pembrolizumab were continued to be monitored for AEs.
Arm/Group Title	Pembrolizumab		Control		Placebo Switched to Pembrolizumab Monotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression.		Participants received saline placebo IV PLUS pemetrexed 500 mg/m^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m^2 IV Q3W until progression. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression.		Participants originally randomized to the placebo arm that experienced disease progression were given pembrolizumab 200 mg IV on Day 1 Q3W after the study was unblinded.
All Cause Mortality
	Pembrolizumab		Control		Placebo Switched to Pembrolizumab Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/25 (12%)		7/15 (46.7%)		2/4 (50%)
Serious Adverse Events
	Pembrolizumab		Control		Placebo Switched to Pembrolizumab Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/25 (36%)		6/15 (40%)		1/4 (25%)
Endocrine disorders
Adrenal insufficiency	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
Diarrhoea	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
General disorders
Pyrexia	2/25 (8%)	4	0/15 (0%)	0	0/4 (0%)	0
Hepatobiliary disorders
Hepatic function abnormal	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Infections and infestations
Bacterial infection	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Oesophageal infection	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Parotitis	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Injury, poisoning and procedural complications
Radiation oesophagitis	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Myalgia	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour necrosis	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Nervous system disorders
Brain oedema	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Cerebral haemorrhage	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Polyneuropathy	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease	0/25 (0%)	0	2/15 (13.3%)	2	0/4 (0%)	0
Pneumonitis	1/25 (4%)	1	0/15 (0%)	0	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Toxic epidermal necrolysis	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Vascular disorders
Deep vein thrombosis	1/25 (4%)	1	0/15 (0%)	0	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	Pembrolizumab		Control		Placebo Switched to Pembrolizumab Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/25 (100%)		15/15 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Anaemia	11/25 (44%)	17	10/15 (66.7%)	11	0/4 (0%)	0
Leukopenia	0/25 (0%)	0	7/15 (46.7%)	13	0/4 (0%)	0
Neutropenia	3/25 (12%)	5	3/15 (20%)	8	0/4 (0%)	0
Thrombocytopenia	1/25 (4%)	1	4/15 (26.7%)	5	0/4 (0%)	0
Lymphopenia	0/25 (0%)	0	2/15 (13.3%)	3	0/4 (0%)	0
Ear and labyrinth disorders
Hypoacusis	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Tinnitus	3/25 (12%)	3	1/15 (6.7%)	2	0/4 (0%)	0
Endocrine disorders
Hypothyroidism	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Hyperthyroidism	2/25 (8%)	2	0/15 (0%)	0	0/4 (0%)	0
Eye disorders
Lacrimation increased	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Conjunctivitis allergic	0/25 (0%)	0	1/15 (6.7%)	2	0/4 (0%)	0
Dry eye	2/25 (8%)	3	0/15 (0%)	0	0/4 (0%)	0
Periorbital oedema	3/25 (12%)	3	0/15 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
Constipation	16/25 (64%)	22	11/15 (73.3%)	18	0/4 (0%)	0
Diarrhoea	8/25 (32%)	9	2/15 (13.3%)	3	1/4 (25%)	1
Dry mouth	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Nausea	18/25 (72%)	41	8/15 (53.3%)	19	1/4 (25%)	1
Stomatitis	7/25 (28%)	9	4/15 (26.7%)	7	0/4 (0%)	0
Vomiting	2/25 (8%)	4	4/15 (26.7%)	6	0/4 (0%)	0
Bowel movement irregularity	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Dental caries	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
Large intestine polyp	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Oral hyperaesthesia	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
General disorders
Face oedema	5/25 (20%)	6	1/15 (6.7%)	1	0/4 (0%)	0
Fatigue	4/25 (16%)	4	5/15 (33.3%)	7	0/4 (0%)	0
Infusion site extravasation	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
Localised oedema	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Malaise	5/25 (20%)	8	4/15 (26.7%)	6	0/4 (0%)	0
Oedema peripheral	2/25 (8%)	2	5/15 (33.3%)	6	0/4 (0%)	0
Puncture site pain	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Pyrexia	3/25 (12%)	7	1/15 (6.7%)	1	1/4 (25%)	1
Hepatobiliary disorders
Hepatic function abnormal	2/25 (8%)	2	0/15 (0%)	0	0/4 (0%)	0
Infections and infestations
Conjunctivitis	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
Nasopharyngitis	5/25 (20%)	11	1/15 (6.7%)	1	0/4 (0%)	0
Upper respiratory tract infection	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Enterocolitis infectious	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Herpes zoster	2/25 (8%)	2	0/15 (0%)	0	0/4 (0%)	0
Influenza	2/25 (8%)	2	1/15 (6.7%)	1	0/4 (0%)	0
Oral candidiasis	2/25 (8%)	3	0/15 (0%)	0	0/4 (0%)	0
Pharyngitis	2/25 (8%)	2	0/15 (0%)	0	0/4 (0%)	0
Lymph gland infection	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Joint dislocation	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Wound	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Investigations
Alanine aminotransferase increased	9/25 (36%)	14	5/15 (33.3%)	6	0/4 (0%)	0
Aspartate aminotransferase increased	8/25 (32%)	11	5/15 (33.3%)	6	0/4 (0%)	0
Blood creatinine increased	2/25 (8%)	4	1/15 (6.7%)	1	0/4 (0%)	0
Weight increased	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
White blood cell count decreased	10/25 (40%)	20	3/15 (20%)	4	0/4 (0%)	0
Blood bilirubin increased	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Creatinine renal clearance decreased	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
Lymphocyte count decreased	7/25 (28%)	19	1/15 (6.7%)	2	0/4 (0%)	0
Neutrophil count decreased	7/25 (28%)	14	2/15 (13.3%)	2	0/4 (0%)	0
Platelet count decreased	3/25 (12%)	3	2/15 (13.3%)	5	0/4 (0%)	0
Thyroid hormones decreased	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Thyroxine free increased	2/25 (8%)	2	0/15 (0%)	0	0/4 (0%)	0
Tri-iodothyronine free decreased	2/25 (8%)	3	0/15 (0%)	0	0/4 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	14/25 (56%)	20	9/15 (60%)	23	0/4 (0%)	0
Hyperglycaemia	2/25 (8%)	3	1/15 (6.7%)	1	0/4 (0%)	0
Hyperkalaemia	2/25 (8%)	3	1/15 (6.7%)	1	0/4 (0%)	0
Hyperuricaemia	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Hypoglycaemia	0/25 (0%)	0	1/15 (6.7%)	2	0/4 (0%)	0
Diabetes mellitus	3/25 (12%)	3	0/15 (0%)	0	0/4 (0%)	0
Hypokalaemia	2/25 (8%)	2	0/15 (0%)	0	0/4 (0%)	0
Hyponatraemia	3/25 (12%)	3	1/15 (6.7%)	1	1/4 (25%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Back pain	4/25 (16%)	4	2/15 (13.3%)	2	0/4 (0%)	0
Myalgia	2/25 (8%)	2	0/15 (0%)	0	0/4 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	0/25 (0%)	0	2/15 (13.3%)	2	0/4 (0%)	0
Nervous system disorders
Dizziness	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
Dysgeusia	3/25 (12%)	6	5/15 (33.3%)	9	1/4 (25%)	1
Headache	1/25 (4%)	1	2/15 (13.3%)	3	0/4 (0%)	0
Memory impairment	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Peripheral sensory neuropathy	3/25 (12%)	3	2/15 (13.3%)	2	0/4 (0%)	0
Somnolence	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
Psychiatric disorders
Insomnia	6/25 (24%)	8	1/15 (6.7%)	1	0/4 (0%)	0
Anxiety	1/25 (4%)	2	3/15 (20%)	4	0/4 (0%)	0
Renal and urinary disorders
Dysuria	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Renal impairment	0/25 (0%)	0	1/15 (6.7%)	2	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	2/25 (8%)	2	1/15 (6.7%)	1	0/4 (0%)	0
Hiccups	7/25 (28%)	11	5/15 (33.3%)	5	1/4 (25%)	1
Rhinitis allergic	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	4/25 (16%)	5	1/15 (6.7%)	1	0/4 (0%)	0
Dermatitis acneiform	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
Dry skin	9/25 (36%)	9	2/15 (13.3%)	2	0/4 (0%)	0
Onychoclasis	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Pruritus	1/25 (4%)	1	1/15 (6.7%)	1	0/4 (0%)	0
Rash	6/25 (24%)	6	1/15 (6.7%)	1	1/4 (25%)	1
Rash maculo-papular	2/25 (8%)	4	1/15 (6.7%)	2	0/4 (0%)	0
Vascular disorders
Deep vein thrombosis	0/25 (0%)	0	1/15 (6.7%)	1	0/4 (0%)	0
Hypertension	3/25 (12%)	4	1/15 (6.7%)	1	0/4 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.