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)
Study Details
Study Description
Brief Summary
This is an efficacy and safety study of pembrolizumab (MK-3475) combined with pemetrexed/platinum chemotherapy versus pemetrexed/platinum chemotherapy alone in 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 10 (effective date 23-Dec-2019), active participants, investigator, and sponsor personnel or delegate(s) involved in the treatment administration or clinical evaluation of the participants will be unblinded, and all participants in the 'control' arm will discontinue saline placebo.
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 |
|---|---|---|
|
Phase 3 |
Study Design
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. |
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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurs, participants may be able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression. |
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
- 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 08-Nov-2017 (Up to approximately 21 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.
- Overall Survival (OS) [Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)]
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS is presented.
Secondary Outcome Measures
- Overall Response Rate (ORR) Per RECIST 1.1 as Assessed by Blinded Central Imaging [Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 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.
- 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 08-Nov-2017 (Up to approximately 21 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 to be 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.
- Number of Participants Who Experienced an Adverse Event (AE) [Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months); Serious AEs: Up to 90 days after last dose of study treatment, Other AEs: Up to 30 days after last dose of study treatment]
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. For participants who switched from the Control group to receiving pembro, AEs that occurred after the first dose of pembro are excluded from this interim analysis, but will be included in the final analysis. The number of participants who experienced an AE is presented.
- Number of Participants Who Discontinued Any Study Drug Due to an AE [Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months)]
The number of participants who discontinued any randomized study drug due to an AE is presented.
Other Outcome Measures
- Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria [Up to 24 months]
Eligibility Criteria
Criteria
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 interstitial lung disease or a history of pneumonitis that required oral of IV glucocorticoids to assist with management.
-
Is pregnant or breastfeeding, or expecting to conceive or father children prior to 120 days after the last dose of study medication or through 180 days after last dose of chemotherapeutic agents.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 3475-189
- 163421
- MK-3475-189
- 2015-003694-15
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | These interim results are based on a database cutoff date of 08-Nov-2017, at which time 372 participants were ongoing in the study. 67 participants randomized to receiving Control treatment had switched to receiving pembrolizumab monotherapy treatment. These interim results are for randomized treatment only. |
| Arm/Group Title | Pembrolizumab | Control |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab (pembro) 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 pembro 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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. 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 | 410 | 206 |
| Treated | 405 | 202 |
| Switched to Pembrolizumab | 0 | 67 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 410 | 206 |
Baseline Characteristics
| Arm/Group Title | Pembrolizumab | Control | Total |
|---|---|---|---|
| Arm/Group Description | Participants received pembro 200 mg 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 pembro 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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. 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 | 410 | 206 | 616 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
63.2
(9.4)
|
62.8
(9.1)
|
63.1
(9.3)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
156
38%
|
97
47.1%
|
253
41.1%
|
| Male |
254
62%
|
109
52.9%
|
363
58.9%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
10
2.4%
|
8
3.9%
|
18
2.9%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
11
2.7%
|
3
1.5%
|
14
2.3%
|
| White |
387
94.4%
|
194
94.2%
|
581
94.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
2
0.5%
|
1
0.5%
|
3
0.5%
|
| Programmed Cell Death-Ligand 1 (PD-L1) Tumor Status (Count of Participants) | |||
| TPS <1% |
127
31%
|
63
30.6%
|
190
30.8%
|
| TPS ≥1% |
260
63.4%
|
128
62.1%
|
388
63%
|
| Not Evaluable |
23
5.6%
|
15
7.3%
|
38
6.2%
|
| Platinum Chemotherapy (Count of Participants) | |||
| Cisplatin |
113
27.6%
|
58
28.2%
|
171
27.8%
|
| Carboplatin |
297
72.4%
|
148
71.8%
|
445
72.2%
|
| Smoking Status (Count of Participants) | |||
| Never Smoker |
48
11.7%
|
25
12.1%
|
73
11.9%
|
| Former/Current Smoker |
362
88.3%
|
181
87.9%
|
543
88.1%
|
Outcome Measures
| 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 08-Nov-2017 (Up to approximately 21 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 pembro 200 mg 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 pembro 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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. 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 | 410 | 206 |
| Median (95% Confidence Interval) [Months] |
8.8
|
4.9
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Control |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.00001 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.52 | |
| Confidence Interval |
(2-Sided) 95% 0.43 to 0.64 |
|
| 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. | |
| 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 interim analysis were censored at the date of the last follow-up. The OS is presented. |
| Time Frame | Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 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 pembro 200 mg 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 pembro 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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. 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 | 410 | 206 |
| Median (95% Confidence Interval) [Months] |
NA
|
11.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Control |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.00001 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.49 | |
| Confidence Interval |
(2-Sided) 95% 0.38 to 0.64 |
|
| 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. | |
| 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 08-Nov-2017 (Up to approximately 21 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 pembro 200 mg 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 pembro 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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. 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 | 410 | 206 |
| Number (95% Confidence Interval) [Percentage of Participants] |
47.6
11.6%
|
18.9
9.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab, Control |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | H0:Difference in percentages=0 vs H1:Difference in percentages>0 | |
| Method | Stratified Miettinen and Nurminen | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentage vs. Control |
| Estimated Value | 28.5 | |
| Confidence Interval |
(2-Sided) 95% 21.1 to 35.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Miettinen and Nurminen method 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. | |
| 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 to be 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 08-Nov-2017 (Up to approximately 21 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 pembro 200 mg 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 pembro 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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. 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 | 195 | 39 |
| Median (Full Range) [Months] |
11.2
|
7.8
|
| 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. For participants who switched from the Control group to receiving pembro, AEs that occurred after the first dose of pembro are excluded from this interim analysis, but will be included in the final analysis. The number of participants who experienced an AE is presented. |
| Time Frame | Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 months); Serious AEs: Up to 90 days after last dose of study treatment, Other AEs: Up to 30 days after last dose of study treatment |
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 pembro 200 mg 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 pembro 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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. 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 | 405 | 202 |
| Count of Participants [Participants] |
404
98.5%
|
200
97.1%
|
| 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 | Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 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 pembro 200 mg 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 pembro 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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. 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 | 405 | 202 |
| Count of Participants [Participants] |
112
27.3%
|
30
14.6%
|
| Title | Progression-Free Survival (PFS) as Assessed by Investigator Immune-related RECIST (irRECIST) Response Criteria |
|---|---|
| Description | |
| Time Frame | Up to 24 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | Through Database Cutoff Date of 08-Nov-2017 (Up to approximately 21 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. For participants who switched from the Control group to receiving pembro, AEs occurring after 1st pembro dose are excluded from this interim analysis. | |||
| Arm/Group Title | Pembrolizumab | Control | ||
| Arm/Group Description | Participants received pembro 200 mg 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 pembro 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. With Amendment 10 (effective date: 23-Dec-2019), all participants will discontinue saline placebo. If documented progression occurred, participants may have been able to receive pembrolizumab Q3W for the remainder of the study or until documented further progression. | ||
All Cause Mortality |
||||
| Pembrolizumab | Control | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 124/405 (30.6%) | 105/202 (52%) | ||
Serious Adverse Events |
||||
| Pembrolizumab | Control | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 202/405 (49.9%) | 95/202 (47%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 12/405 (3%) | 13 | 10/202 (5%) | 11 |
| Disseminated intravascular coagulation | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Febrile neutropenia | 23/405 (5.7%) | 25 | 4/202 (2%) | 4 |
| Leukopenia | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Neutropenia | 10/405 (2.5%) | 10 | 1/202 (0.5%) | 1 |
| Pancytopenia | 4/405 (1%) | 4 | 2/202 (1%) | 3 |
| Thrombocytopenia | 13/405 (3.2%) | 14 | 5/202 (2.5%) | 5 |
| Cardiac disorders | ||||
| Acute myocardial infarction | 1/405 (0.2%) | 2 | 0/202 (0%) | 0 |
| Atrial fibrillation | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Atrial flutter | 0/405 (0%) | 0 | 2/202 (1%) | 2 |
| Cardiac arrest | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Cardiac failure | 3/405 (0.7%) | 3 | 0/202 (0%) | 0 |
| Cardiopulmonary failure | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Myocardial infarction | 3/405 (0.7%) | 3 | 0/202 (0%) | 0 |
| Pericardial effusion | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Pericarditis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Sinus tachycardia | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Stress cardiomyopathy | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Supraventricular tachycardia | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Tachyarrhythmia | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Ventricular arrhythmia | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Endocrine disorders | ||||
| Adrenal insufficiency | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Hypothyroidism | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Abdominal pain upper | 1/405 (0.2%) | 1 | 2/202 (1%) | 2 |
| Colitis | 3/405 (0.7%) | 3 | 0/202 (0%) | 0 |
| Constipation | 3/405 (0.7%) | 3 | 0/202 (0%) | 0 |
| Diarrhoea | 15/405 (3.7%) | 17 | 6/202 (3%) | 9 |
| Duodenitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Gastroduodenitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Gastrointestinal perforation | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Impaired gastric emptying | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Intestinal ischaemia | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Intestinal pseudo-obstruction | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Intussusception | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Lip oedema | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Mesenteric artery embolism | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Nausea | 4/405 (1%) | 4 | 6/202 (3%) | 6 |
| Neutropenic colitis | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Oesophageal stenosis | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Oesophagitis | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Pancreatitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Pancreatitis acute | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Pancreatitis chronic | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Small intestinal haemorrhage | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Stomatitis | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Vomiting | 8/405 (2%) | 9 | 5/202 (2.5%) | 5 |
| General disorders | ||||
| Asthenia | 7/405 (1.7%) | 7 | 0/202 (0%) | 0 |
| Chest pain | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Death | 3/405 (0.7%) | 3 | 1/202 (0.5%) | 1 |
| Fatigue | 3/405 (0.7%) | 3 | 0/202 (0%) | 0 |
| General physical health deterioration | 4/405 (1%) | 4 | 2/202 (1%) | 3 |
| Influenza like illness | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Localised oedema | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Malaise | 1/405 (0.2%) | 1 | 2/202 (1%) | 2 |
| Mucosal inflammation | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Multiple organ dysfunction syndrome | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Oedema peripheral | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Pyrexia | 9/405 (2.2%) | 10 | 3/202 (1.5%) | 3 |
| Hepatobiliary disorders | ||||
| Autoimmune hepatitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Bile duct stone | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Cholangitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Cholangitis sclerosing | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Cholecystitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Hepatitis | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Hepatotoxicity | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Immune system disorders | ||||
| Cytokine release syndrome | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Infections and infestations | ||||
| Abdominal sepsis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Bacteraemia | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Bacterial colitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Bronchitis | 4/405 (1%) | 4 | 2/202 (1%) | 2 |
| CNS ventriculitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Cellulitis | 5/405 (1.2%) | 6 | 1/202 (0.5%) | 2 |
| Clostridium difficile colitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Diverticulitis | 1/405 (0.2%) | 2 | 1/202 (0.5%) | 1 |
| Empyema | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Endocarditis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Erysipelas | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Folliculitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Gastroenteritis | 3/405 (0.7%) | 3 | 0/202 (0%) | 0 |
| Herpes zoster | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Infected dermal cyst | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Infection | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Infectious pleural effusion | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Influenza | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Kidney infection | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Lower respiratory tract infection | 2/405 (0.5%) | 2 | 3/202 (1.5%) | 3 |
| Lung abscess | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Lung infection | 3/405 (0.7%) | 3 | 0/202 (0%) | 0 |
| Neutropenic sepsis | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Oral candidiasis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Otitis media | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Peritonitis | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Pneumocystis jirovecii pneumonia | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Pneumonia | 23/405 (5.7%) | 23 | 17/202 (8.4%) | 19 |
| Pneumonia bacterial | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Pulmonary sepsis | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Respiratory tract infection | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Salmonella bacteraemia | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Sepsis | 5/405 (1.2%) | 5 | 2/202 (1%) | 2 |
| Septic shock | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Tuberculosis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Tuberculous pleurisy | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Upper respiratory tract infection | 6/405 (1.5%) | 6 | 2/202 (1%) | 5 |
| Urinary tract infection | 4/405 (1%) | 4 | 1/202 (0.5%) | 1 |
| Injury, poisoning and procedural complications | ||||
| Accidental overdose | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Craniocerebral injury | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Fall | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Femoral neck fracture | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Femur fracture | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Limb traumatic amputation | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Lumbar vertebral fracture | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Spinal compression fracture | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Spinal fracture | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Toxicity to various agents | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Upper limb fracture | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Investigations | ||||
| Alanine aminotransferase increased | 0/405 (0%) | 0 | 2/202 (1%) | 2 |
| Blood calcium decreased | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Blood creatinine increased | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Blood magnesium decreased | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| C-reactive protein increased | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Hepatic enzyme increased | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Platelet count decreased | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Metabolism and nutrition disorders | ||||
| Dehydration | 5/405 (1.2%) | 6 | 2/202 (1%) | 2 |
| Hyperglycaemia | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Hypokalaemia | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Hypomagnesaemia | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Hyponatraemia | 1/405 (0.2%) | 1 | 2/202 (1%) | 2 |
| Type 1 diabetes mellitus | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Type 2 diabetes mellitus | 2/405 (0.5%) | 3 | 0/202 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 5/405 (1.2%) | 5 | 0/202 (0%) | 0 |
| Back pain | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 2 |
| Flank pain | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Groin pain | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Hypertrophic osteoarthropathy | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Muscle haemorrhage | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Muscular weakness | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Musculoskeletal chest pain | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Myalgia | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Pain in extremity | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Pathological fracture | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Cancer pain | 3/405 (0.7%) | 3 | 2/202 (1%) | 2 |
| Malignant neoplasm progression | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Metastases to central nervous system | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Thyroid cancer | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Tracheal neoplasm | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Tumour pain | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Nervous system disorders | ||||
| Balance disorder | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Brain stem infarction | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Cerebral haemorrhage | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Cerebral infarction | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Cerebrovascular accident | 3/405 (0.7%) | 3 | 0/202 (0%) | 0 |
| Dizziness | 4/405 (1%) | 4 | 1/202 (0.5%) | 1 |
| Encephalopathy | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Haemorrhage intracranial | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Hydrocephalus | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Ischaemic stroke | 2/405 (0.5%) | 3 | 1/202 (0.5%) | 1 |
| Lacunar stroke | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Lumbar radiculopathy | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Partial seizures | 0/405 (0%) | 0 | 1/202 (0.5%) | 2 |
| Seizure | 2/405 (0.5%) | 2 | 1/202 (0.5%) | 1 |
| Syncope | 2/405 (0.5%) | 2 | 2/202 (1%) | 2 |
| Transient ischaemic attack | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Vasculitis cerebral | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Product Issues | ||||
| Device dislocation | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Psychiatric disorders | ||||
| Anxiety | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Confusional state | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Delirium | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Disorientation | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Major depression | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Renal and urinary disorders | ||||
| Acute kidney injury | 8/405 (2%) | 8 | 0/202 (0%) | 0 |
| Acute prerenal failure | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Autoimmune nephritis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Haematuria | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Nephritis | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Prerenal failure | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Renal failure | 1/405 (0.2%) | 1 | 2/202 (1%) | 2 |
| Renal tubular necrosis | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Tubulointerstitial nephritis | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Urinary tract obstruction | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Reproductive system and breast disorders | ||||
| Balanoposthitis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Acute respiratory failure | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Atelectasis | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Chronic obstructive pulmonary disease | 4/405 (1%) | 5 | 3/202 (1.5%) | 3 |
| Dyspnoea | 5/405 (1.2%) | 5 | 5/202 (2.5%) | 6 |
| Epistaxis | 1/405 (0.2%) | 1 | 1/202 (0.5%) | 1 |
| Haemoptysis | 3/405 (0.7%) | 3 | 2/202 (1%) | 2 |
| Haemothorax | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Hiccups | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Obstructive airways disorder | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Pleural effusion | 6/405 (1.5%) | 7 | 4/202 (2%) | 4 |
| Pneumonia aspiration | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Pneumonitis | 12/405 (3%) | 13 | 4/202 (2%) | 4 |
| Pneumothorax | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Pulmonary embolism | 5/405 (1.2%) | 5 | 4/202 (2%) | 4 |
| Respiratory failure | 1/405 (0.2%) | 1 | 3/202 (1.5%) | 3 |
| Skin and subcutaneous tissue disorders | ||||
| Dermatitis | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Diabetic foot | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Rash | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Rash papular | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Skin sensitisation | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Vascular disorders | ||||
| Deep vein thrombosis | 2/405 (0.5%) | 2 | 2/202 (1%) | 2 |
| Hypertension | 2/405 (0.5%) | 2 | 0/202 (0%) | 0 |
| Jugular vein thrombosis | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
| Peripheral artery occlusion | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Vena cava thrombosis | 1/405 (0.2%) | 1 | 0/202 (0%) | 0 |
| Venous occlusion | 0/405 (0%) | 0 | 1/202 (0.5%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Pembrolizumab | Control | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 393/405 (97%) | 196/202 (97%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 178/405 (44%) | 227 | 88/202 (43.6%) | 112 |
| Leukopenia | 23/405 (5.7%) | 26 | 13/202 (6.4%) | 17 |
| Neutropenia | 104/405 (25.7%) | 192 | 48/202 (23.8%) | 91 |
| Thrombocytopenia | 64/405 (15.8%) | 100 | 25/202 (12.4%) | 36 |
| Endocrine disorders | ||||
| Hypothyroidism | 26/405 (6.4%) | 34 | 5/202 (2.5%) | 5 |
| Eye disorders | ||||
| Lacrimation increased | 69/405 (17%) | 76 | 22/202 (10.9%) | 23 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 29/405 (7.2%) | 37 | 11/202 (5.4%) | 11 |
| Abdominal pain upper | 24/405 (5.9%) | 26 | 2/202 (1%) | 2 |
| Constipation | 139/405 (34.3%) | 199 | 64/202 (31.7%) | 83 |
| Diarrhoea | 115/405 (28.4%) | 156 | 40/202 (19.8%) | 50 |
| Dyspepsia | 24/405 (5.9%) | 29 | 11/202 (5.4%) | 11 |
| Nausea | 223/405 (55.1%) | 392 | 101/202 (50%) | 180 |
| Stomatitis | 35/405 (8.6%) | 44 | 15/202 (7.4%) | 20 |
| Vomiting | 94/405 (23.2%) | 160 | 43/202 (21.3%) | 66 |
| General disorders | ||||
| Asthenia | 77/405 (19%) | 121 | 49/202 (24.3%) | 80 |
| Chest pain | 34/405 (8.4%) | 38 | 11/202 (5.4%) | 13 |
| Fatigue | 164/405 (40.5%) | 258 | 77/202 (38.1%) | 126 |
| Mucosal inflammation | 35/405 (8.6%) | 45 | 15/202 (7.4%) | 22 |
| Oedema peripheral | 78/405 (19.3%) | 106 | 26/202 (12.9%) | 35 |
| Pyrexia | 74/405 (18.3%) | 97 | 27/202 (13.4%) | 40 |
| Infections and infestations | ||||
| Conjunctivitis | 31/405 (7.7%) | 40 | 17/202 (8.4%) | 31 |
| Nasopharyngitis | 30/405 (7.4%) | 40 | 10/202 (5%) | 12 |
| Upper respiratory tract infection | 35/405 (8.6%) | 41 | 14/202 (6.9%) | 15 |
| Urinary tract infection | 28/405 (6.9%) | 40 | 11/202 (5.4%) | 16 |
| Investigations | ||||
| Alanine aminotransferase increased | 49/405 (12.1%) | 62 | 17/202 (8.4%) | 21 |
| Aspartate aminotransferase increased | 38/405 (9.4%) | 49 | 13/202 (6.4%) | 14 |
| Blood creatinine increased | 46/405 (11.4%) | 69 | 16/202 (7.9%) | 24 |
| Weight decreased | 37/405 (9.1%) | 40 | 15/202 (7.4%) | 16 |
| White blood cell count decreased | 26/405 (6.4%) | 45 | 13/202 (6.4%) | 20 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 114/405 (28.1%) | 149 | 61/202 (30.2%) | 79 |
| Hyperglycaemia | 27/405 (6.7%) | 45 | 6/202 (3%) | 9 |
| Hypokalaemia | 43/405 (10.6%) | 70 | 14/202 (6.9%) | 17 |
| Hypomagnesaemia | 31/405 (7.7%) | 43 | 8/202 (4%) | 13 |
| Hypophosphataemia | 21/405 (5.2%) | 29 | 5/202 (2.5%) | 7 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 33/405 (8.1%) | 43 | 17/202 (8.4%) | 20 |
| Back pain | 52/405 (12.8%) | 61 | 22/202 (10.9%) | 23 |
| Musculoskeletal pain | 25/405 (6.2%) | 32 | 17/202 (8.4%) | 19 |
| Pain in extremity | 29/405 (7.2%) | 32 | 17/202 (8.4%) | 17 |
| Nervous system disorders | ||||
| Dizziness | 45/405 (11.1%) | 48 | 18/202 (8.9%) | 19 |
| Dysgeusia | 46/405 (11.4%) | 52 | 19/202 (9.4%) | 20 |
| Headache | 48/405 (11.9%) | 57 | 19/202 (9.4%) | 23 |
| Paraesthesia | 20/405 (4.9%) | 27 | 12/202 (5.9%) | 18 |
| Psychiatric disorders | ||||
| Insomnia | 24/405 (5.9%) | 29 | 14/202 (6.9%) | 14 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 87/405 (21.5%) | 112 | 57/202 (28.2%) | 63 |
| Dyspnoea | 82/405 (20.2%) | 98 | 47/202 (23.3%) | 57 |
| Epistaxis | 29/405 (7.2%) | 35 | 7/202 (3.5%) | 11 |
| Haemoptysis | 11/405 (2.7%) | 13 | 14/202 (6.9%) | 15 |
| Oropharyngeal pain | 21/405 (5.2%) | 24 | 4/202 (2%) | 4 |
| Productive cough | 21/405 (5.2%) | 24 | 11/202 (5.4%) | 12 |
| Rhinorrhoea | 22/405 (5.4%) | 24 | 9/202 (4.5%) | 9 |
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 21/405 (5.2%) | 22 | 9/202 (4.5%) | 9 |
| Dry skin | 18/405 (4.4%) | 19 | 18/202 (8.9%) | 18 |
| Erythema | 21/405 (5.2%) | 24 | 4/202 (2%) | 5 |
| Pruritus | 43/405 (10.6%) | 55 | 21/202 (10.4%) | 22 |
| Rash | 81/405 (20%) | 108 | 23/202 (11.4%) | 28 |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Senior Vice President, Global Clinical Development |
|---|---|
| Organization | Merck Sharp & Dohme LLC |
| Phone | 1-800-672-6372 |
| ClinicalTrialsDisclosure@merck.com |
- 3475-189
- 163421
- MK-3475-189
- 2015-003694-15