Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426)
Study Details
Study Description
Brief Summary
The purpose of this study is to evaluate the efficacy and safety of pembrolizumab (MK-3475) in combination with axitinib versus sunitinib monotherapy as a first-line treatment for participants with advanced/metastatic renal cell carcinoma (mRCC).
The primary hypotheses of this study are:
-
The combination therapy of pembrolizumab plus axitinib is superior to sunitinib monotherapy with respect to Progression-Free Survival (PFS) as assessed by blinded independent central imaging review per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
-
The combination therapy of pembrolizumab plus axitinib is superior to sunitinib monotherapy with respect to Overall Survival (OS).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Pembrolizumab+Axitinib Combination Therapy Participants receive pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. |
Biological: Pembrolizumab
Intravenous infusion
Other Names:
Drug: Axitinib
Oral tablet
Other Names:
|
| Active Comparator: Sunitinib Monotherapy Participants receive sunitinib 50 mg orally once daily for 4 weeks and then are off treatment for 2 weeks. |
Drug: Sunitinib
Oral capsule
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review [Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 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. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The PFS for participants is presented.
- Overall Survival (OS) [Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 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 was calculated using the product-limit (Kaplan-Meier) method for censored data. The OS for participants is presented.
Secondary Outcome Measures
- Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review [Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)]
ORR was determined per RECIST 1.1 and 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 ORR was calculated using the Miettinen & Nurminen method stratified by International Metastatic Renal Cell Carcinoma (RCC) Database Consortium (IMDC) risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). The percentage of participants who experienced a CR or PR is presented.
- Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review [Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)]
DCR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions), Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters), or Stable Disease (SD) per RECIST 1.1 for ≥6 months. The DCR was calculated using the Miettinen & Nurminen method stratified by International Metastatic Renal Cell Carcinoma (RCC) Database Consortium (IMDC) risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). The percentage of participants who experienced a CR, PR, or SD is presented.
- Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review [Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)]
DOR was defined as the time from first documented evidence of a Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 until progressive disease (PD) or death due to any cause, whichever occurred first. PD was defined per RECIST 1.1 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. The appearance of one or more new lesions was also considered PD. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data. The DOR for all participants who experienced a CR or PR is presented.
- Number of Participants Who Experienced an Adverse Event (AE) [Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)]
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented.
- Number of Participants Who Discontinued Study Drug Due to an AE [Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)]
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented.
- Progression Free Survival Rate (PFS Rate) at Month 12 in All Participants [Month 12]
The PFS rate was determined in all participants at Month 12. 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 Response Evaluation Criteria in Solid Tumors Version 1.1 (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. The appearance of one or more new lesions was also considered PD. The date of PD was approximated by the date of the first assessment at which PD was documented per RECIST 1.1 by Blinded Independent Central Review (BICR). Death was always considered as confirmed PD. Participants who did not experience PFS were censored at the last disease assessment. The PFS rate at Month 12 is presented.
- Progression Free Survival Rate (PFS Rate) at Month 18 in All Participants [Month 18]
The PFS rate was determined in all participants at Month 18. 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 Response Evaluation Criteria in Solid Tumors Version 1.1 (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. The appearance of one or more new lesions was also considered PD. The date of PD was approximated by the date of the first assessment at which PD was documented per RECIST 1.1 by Blinded Independent Central Review (BICR). Death was always considered as confirmed PD. Participants who did not experience PFS were censored at the last disease assessment. The PFS rate at Month 18 is presented.
- Progression Free Survival Rate (PFS Rate) at Month 24 in All Participants [Month 24]
The PFS rate was determined in all participants at Month 24. 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 Response Evaluation Criteria in Solid Tumors Version 1.1 (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. The appearance of one or more new lesions was also considered PD. The date of PD was approximated by the date of the first assessment at which PD was documented per RECIST 1.1 by Blinded Independent Central Review (BICR). Death was always considered as confirmed PD. Participants who did not experience PFS were censored at the last disease assessment.
- Overall Survival (OS) Rate at Month 12 in All Participants [Month 12]
The OS rate was determined for all participants at Month 12 and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last assessment. The OS rate at Month 12 is presented.
- Overall Survival (OS) Rate at Month 18 in All Participants [Month 18]
The OS rate was determined for all participants at Month 18 and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last assessment. The OS rate at Month 18 is presented.
- Overall Survival (OS) Rate at Month 24 in All Participants [Month 24]
The OS rate was determined for all participants at Month 24 and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last assessment.
- Time to True Deterioration (TTD) of the Functional Assessment of Cancer Therapy Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS) Score [Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months)]
TTD was defined as time (in months) from the first dose of study treatment to the date of deterioration of FKSI-DRS Score. The FKSI-DRS was a questionnaire that asked the participant to rate 9 kidney cancer-related symptoms: lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or blood in the urine. Each item was scored on a 5-point scale (0=not at all to 4=very much). FKSI-DRS total score ranged from 0 (most severe symptoms) to 36 (no symptoms) with a higher score indicating a better outcome. Deterioration was defined as a 3-point decrease (i.e. lower score) in symptom score and the time to true deterioration was the time to first onset of 3 or more decreases from baseline with confirmation under right-censoring rule (the last observation). The time to true deterioration as measured in months is presented.
- Least Squares (LS) Mean Change From Baseline to Week 54 in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (GHS) Scale Score [Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 54]
EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status.
Other Outcome Measures
- Mean Baseline EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Score [Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days])]
EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. The mean baseline EORTC QLQ-C30 score is presented.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Has histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features
-
Has locally advanced/metastatic disease (i.e., newly diagnosed Stage IV RCC per American Joint Committee on Cancer) or has recurrent disease
-
Has measurable disease per RECIST 1.1 as assessed by the investigator/site radiologist
-
Has received no prior systemic therapy for advanced RCC.
-
Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
-
Has Karnofsky performance status (KPS) ≥ 70% as assessed within 10 days prior to randomization.
-
If receiving bone resorptive therapy (including but not limited to bisphosphonate or RANK-L inhibitor) must have therapy initiated at least 2 weeks prior to randomization.
-
Demonstrates adequate organ function.
-
Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug.
-
Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study drug through 120 days after the last dose of study drug.
Exclusion Criteria:
-
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization.
-
Has had major surgery within 4 weeks, received radiation therapy within 2 weeks prior to randomization, or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to prior treatment.
-
Has had prior treatment with any anti-programmed cell death (anti-PD-1), or programmed cell death ligand 1 (PD-L1), or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms.
-
Has received prior systemic anti-cancer therapy for RCC with vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) or mechanistic target of rapamycin (mTOR) targeting agents.
-
Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to axitinib or sunitinib.
-
Has a diagnosis of immunodeficiency OR is receiving a systemic steroid therapy exceeding physiologic corticosteroid dose or any other form of immunosuppressive therapy within 7 days prior to randomization, except in the case of central nervous system (CNS) metastases.
-
Has an active autoimmune disease requiring systemic treatment with in the past 2 years OR a documented history of clinically severe autoimmune disease. Note: Participants with vitiligo, Sjøgren's syndrome, Type 1 diabetes, resolved childhood asthma/atopy, hypothyroidism or adrenal or pituitary insufficiency who are stable on hormone replacement, are not excluded.
-
Has a known additional malignancy that has progressed or has required active treatment in the last 3 years. Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ such as breast cancer in situ are acceptable if they have undergone potentially curative therapy.
-
Has known active CNS metastases and/or carcinomatous meningitis.
-
Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
-
Has an active infection requiring systemic therapy.
-
Has a known history of Human Immunodeficiency Virus (HIV).
-
Has known active Hepatitis B or Hepatitis C infection.
-
Has received a live virus vaccine within 30 days of randomization.
-
Has a clinically significant gastrointestinal (GI) abnormality including:
-
Malabsorption, total gastric resection
-
Or any condition that might affect the absorption of orally taken medication
-
Active GI bleeding, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy
-
Intraluminal metastatic lesion with suspected bleeding, inflammatory bowel disease, ulcerative colitis or other GI condition associated with increased risk of perforation
-
Has QT interval corrected for heart rate (QTc) ≥480 msec.
-
Has a history of any of the following cardiovascular conditions within 12 months of randomization:
-
Myocardial infarction
-
Unstable angina pectoris
-
Cardiac angioplasty or stenting
-
Coronary/peripheral artery bypass graft
-
Class III or IV congestive heart failure per New York Heart Association
-
Cerebrovascular accident or transient ischemic attack
-
Has a history of deep vein thrombosis or pulmonary embolism within 6 months of screening.
-
Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥150 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg.
-
Has evidence of inadequate wound healing.
-
Has active bleeding disorder or other history of significant bleeding episodes within 30 days of randomization.
-
Has hemoptysis within 6 weeks prior to randomization.
-
Has current use (within 7 days of randomization) or anticipated need for treatment with drugs or foods that are known strong cytochrome P450 (CYP3A4/5) inhibitors.
-
Has current use (within 7 days of randomization) or anticipated need for treatment with drugs that are known strong CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort; or drugs that are known with proarrhythmic potential.
-
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
-
Has had a prior solid organ transplant.
-
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug.
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.- 3475-426
- 2016-000588-17
- 163460
- MK-3475-426
- KEYNOTE-426
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | These interim results are based on a database cutoff date of 24-Aug-2018, at which time 693 participants were ongoing in the study. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Period Title: Overall Study | ||
| STARTED | 432 | 429 |
| Treated | 429 | 425 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 432 | 429 |
Baseline Characteristics
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib | Total |
|---|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. | Total of all reporting groups |
| Overall Participants | 432 | 429 | 861 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
61.2
(10.0)
|
60.8
(10.2)
|
61.0
(10.1)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
124
28.7%
|
109
25.4%
|
233
27.1%
|
| Male |
308
71.3%
|
320
74.6%
|
628
72.9%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
19
4.4%
|
18
4.2%
|
37
4.3%
|
| Not Hispanic or Latino |
377
87.3%
|
387
90.2%
|
764
88.7%
|
| Unknown or Not Reported |
36
8.3%
|
24
5.6%
|
60
7%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
66
15.3%
|
71
16.6%
|
137
15.9%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
10
2.3%
|
8
1.9%
|
18
2.1%
|
| White |
343
79.4%
|
341
79.5%
|
684
79.4%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
13
3%
|
9
2.1%
|
22
2.6%
|
| International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Risk Group (Count of Participants) | |||
| Favorable |
138
31.9%
|
131
30.5%
|
269
31.2%
|
| Intermediate |
238
55.1%
|
246
57.3%
|
484
56.2%
|
| Poor |
56
13%
|
52
12.1%
|
108
12.5%
|
| Geographic Region (Count of Participants) | |||
| North America |
104
24.1%
|
103
24%
|
207
24%
|
| Western Europe |
106
24.5%
|
104
24.2%
|
210
24.4%
|
| Rest of World |
222
51.4%
|
222
51.7%
|
444
51.6%
|
Outcome Measures
| Title | Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review |
|---|---|
| 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. The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was calculated using the product-limit (Kaplan-Meier) method for censored data. The PFS for participants is presented. |
| Time Frame | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all randomized participants. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 432 | 429 |
| Median (95% Confidence Interval) [Months] |
15.1
|
11.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab + Axitinib, Sunitinib |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.00012 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.69 | |
| Confidence Interval |
(2-Sided) 95% 0.56 to 0.84 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | HR based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by IMDC risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). | |
| 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 was calculated using the product-limit (Kaplan-Meier) method for censored data. The OS for participants is presented. |
| Time Frame | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all randomized participants. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 432 | 429 |
| Median (95% Confidence Interval) [Months] |
NA
|
NA
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab + Axitinib, Sunitinib |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.00005 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.53 | |
| Confidence Interval |
(2-Sided) 95% 0.38 to 0.74 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | HR based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by IMDC risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). | |
| Title | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review |
|---|---|
| Description | ORR was determined per RECIST 1.1 and 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 ORR was calculated using the Miettinen & Nurminen method stratified by International Metastatic Renal Cell Carcinoma (RCC) Database Consortium (IMDC) risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). The percentage of participants who experienced a CR or PR is presented. |
| Time Frame | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all randomized participants. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 432 | 429 |
| Number (95% Confidence Interval) [Percentage of participants] |
59.3
13.7%
|
35.7
8.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab + Axitinib, Sunitinib |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | ||
| Method | Miettinen & Nurminen method | |
| Comments | H0: difference in %=0 versus H1: difference in % >0 | |
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | 23.6 | |
| Confidence Interval |
(2-Sided) 95% 17.2 to 29.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in percentages based on Miettinen & Nurminen method stratified by IMDC risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). | |
| Title | Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review |
|---|---|
| Description | DCR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions), Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters), or Stable Disease (SD) per RECIST 1.1 for ≥6 months. The DCR was calculated using the Miettinen & Nurminen method stratified by International Metastatic Renal Cell Carcinoma (RCC) Database Consortium (IMDC) risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). The percentage of participants who experienced a CR, PR, or SD is presented. |
| Time Frame | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all randomized participants who experienced a PR, CR or SD for ≥6 months. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 432 | 429 |
| Number (95% Confidence Interval) [Percentage of participants] |
71.5
16.6%
|
60.6
14.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pembrolizumab + Axitinib, Sunitinib |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | 11.0 | |
| Confidence Interval |
(2-Sided) 95% 4.8 to 17.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Difference in percentages based on Miettinen & Nurminen method stratified by IMDC risk group (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. Rest of World). | |
| Title | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Imaging Review |
|---|---|
| Description | DOR was defined as the time from first documented evidence of a Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 until progressive disease (PD) or death due to any cause, whichever occurred first. PD was defined per RECIST 1.1 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. The appearance of one or more new lesions was also considered PD. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data. The DOR for all participants who experienced a CR or PR is presented. |
| Time Frame | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all randomized participants who experienced a CR or PR. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 256 | 153 |
| Median (Full Range) [Months] |
NA
|
15.2
|
| Title | Number of Participants Who Experienced an Adverse Event (AE) |
|---|---|
| Description | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented. |
| Time Frame | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all participants who received ≥1 dose of study treatment. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 429 | 425 |
| Count of Participants [Participants] |
422
97.7%
|
423
98.6%
|
| Title | Number of Participants Who Discontinued Study Drug Due to an AE |
|---|---|
| Description | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented. |
| Time Frame | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all participants who received ≥1 dose of study treatment. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 429 | 425 |
| Count of Participants [Participants] |
131
30.3%
|
59
13.8%
|
| Title | Progression Free Survival Rate (PFS Rate) at Month 12 in All Participants |
|---|---|
| Description | The PFS rate was determined in all participants at Month 12. 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 Response Evaluation Criteria in Solid Tumors Version 1.1 (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. The appearance of one or more new lesions was also considered PD. The date of PD was approximated by the date of the first assessment at which PD was documented per RECIST 1.1 by Blinded Independent Central Review (BICR). Death was always considered as confirmed PD. Participants who did not experience PFS were censored at the last disease assessment. The PFS rate at Month 12 is presented. |
| Time Frame | Month 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all randomized participants. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 432 | 429 |
| Number (95% Confidence Interval) [Percentage of participants] |
59.6
13.8%
|
46.1
10.7%
|
| Title | Progression Free Survival Rate (PFS Rate) at Month 18 in All Participants |
|---|---|
| Description | The PFS rate was determined in all participants at Month 18. 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 Response Evaluation Criteria in Solid Tumors Version 1.1 (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. The appearance of one or more new lesions was also considered PD. The date of PD was approximated by the date of the first assessment at which PD was documented per RECIST 1.1 by Blinded Independent Central Review (BICR). Death was always considered as confirmed PD. Participants who did not experience PFS were censored at the last disease assessment. The PFS rate at Month 18 is presented. |
| Time Frame | Month 18 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all randomized participants. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 432 | 429 |
| Number (95% Confidence Interval) [Percentage of participants] |
41.1
9.5%
|
32.8
7.6%
|
| Title | Progression Free Survival Rate (PFS Rate) at Month 24 in All Participants |
|---|---|
| Description | The PFS rate was determined in all participants at Month 24. 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 Response Evaluation Criteria in Solid Tumors Version 1.1 (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. The appearance of one or more new lesions was also considered PD. The date of PD was approximated by the date of the first assessment at which PD was documented per RECIST 1.1 by Blinded Independent Central Review (BICR). Death was always considered as confirmed PD. Participants who did not experience PFS were censored at the last disease assessment. |
| Time Frame | Month 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Overall Survival (OS) Rate at Month 12 in All Participants |
|---|---|
| Description | The OS rate was determined for all participants at Month 12 and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last assessment. The OS rate at Month 12 is presented. |
| Time Frame | Month 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all randomized participants. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 432 | 429 |
| Number (95% Confidence Interval) [Percentage of participants] |
89.9
20.8%
|
78.3
18.3%
|
| Title | Overall Survival (OS) Rate at Month 18 in All Participants |
|---|---|
| Description | The OS rate was determined for all participants at Month 18 and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last assessment. The OS rate at Month 18 is presented. |
| Time Frame | Month 18 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population consisted of all randomized participants. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 432 | 429 |
| Number (95% Confidence Interval) [Percentage of participants] |
82.3
19.1%
|
72.1
16.8%
|
| Title | Overall Survival (OS) Rate at Month 24 in All Participants |
|---|---|
| Description | The OS rate was determined for all participants at Month 24 and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last assessment. |
| Time Frame | Month 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Time to True Deterioration (TTD) of the Functional Assessment of Cancer Therapy Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS) Score |
|---|---|
| Description | TTD was defined as time (in months) from the first dose of study treatment to the date of deterioration of FKSI-DRS Score. The FKSI-DRS was a questionnaire that asked the participant to rate 9 kidney cancer-related symptoms: lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or blood in the urine. Each item was scored on a 5-point scale (0=not at all to 4=very much). FKSI-DRS total score ranged from 0 (most severe symptoms) to 36 (no symptoms) with a higher score indicating a better outcome. Deterioration was defined as a 3-point decrease (i.e. lower score) in symptom score and the time to true deterioration was the time to first onset of 3 or more decreases from baseline with confirmation under right-censoring rule (the last observation). The time to true deterioration as measured in months is presented. |
| Time Frame | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least 1 dose of study medication and completed at least 1 questionnaire assessment. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 395 | 387 |
| Median (95% Confidence Interval) [Months] |
NA
|
NA
|
| Title | Least Squares (LS) Mean Change From Baseline to Week 54 in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (GHS) Scale Score |
|---|---|
| Description | EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. |
| Time Frame | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 54 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Mean Baseline EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Score |
|---|---|
| Description | EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. The mean baseline EORTC QLQ-C30 score is presented. |
| Time Frame | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants with non-missing questionnaire assessments at baseline. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 394 | 410 |
| Mean (Standard Deviation) [Score on a scale] |
70.90
(21.037)
|
72.07
(20.642)
|
| Title | Least Squares (LS) Mean Change From Baseline to Week 30 in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (GHS) Scale Score |
|---|---|
| Description | EORTC QLQ-C30 is a cancer-specific instrument with 30 questions used to assess the overall quality of life (QOL) in cancer participants. The first 28 questions used a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) for evaluating 5 functional scales (physical, role, social, cognitive, emotional), 8 symptom scales/items (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea and vomiting [N/V], constipation, and pain) and a single item (financial difficulties). The last 2 questions represented the participant's assessment of overall health and quality of life on a 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 global scores were linearly transformed on a scale of 0 to 100; with a high score indicating improved health status. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. The LS Mean change from baseline to Week 30 is presented. |
| Time Frame | Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants who received at least 1 dose of study medication and had non-missing questionnaire assessments at baseline and Week 30. |
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib |
|---|---|---|
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. |
| Measure Participants | 427 | 423 |
| Least Squares Mean (95% Confidence Interval) [Score on a scale] |
-4.05
|
-2.35
|
Adverse Events
| Time Frame | Through Database Cutoff Date of 24-Aug-2018 (up to approximately 22 months) | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Population: All participants who received ≥1 dose of study treatment. 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. | |||
| Arm/Group Title | Pembrolizumab + Axitinib | Sunitinib | ||
| Arm/Group Description | Participants received pembrolizumab 200 mg intravenously every 3 weeks PLUS axitinib 5 mg orally twice daily. | Participants received sunitinib 50 mg orally once daily for 4 weeks and then were off treatment for 2 weeks. | ||
All Cause Mortality |
||||
| Pembrolizumab + Axitinib | Sunitinib | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 59/432 (13.7%) | 97/429 (22.6%) | ||
Serious Adverse Events |
||||
| Pembrolizumab + Axitinib | Sunitinib | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 173/429 (40.3%) | 133/425 (31.3%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 2/429 (0.5%) | 2 | 3/425 (0.7%) | 3 |
| Anaemia of malignant disease | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Cytopenia | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Disseminated intravascular coagulation | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Thrombocytopenia | 0/429 (0%) | 0 | 4/425 (0.9%) | 4 |
| Thrombocytopenic purpura | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Cardiac disorders | ||||
| Acute myocardial infarction | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Angina unstable | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Atrial fibrillation | 4/429 (0.9%) | 4 | 0/425 (0%) | 0 |
| Atrial flutter | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Cardiac amyloidosis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Cardiac arrest | 1/429 (0.2%) | 1 | 2/425 (0.5%) | 2 |
| Cardiac failure | 1/429 (0.2%) | 1 | 2/425 (0.5%) | 3 |
| Cardiac failure acute | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Cardiac failure chronic | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Cardiac failure congestive | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Cardiac tamponade | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Cardiac ventricular thrombosis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Coronary artery occlusion | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Coronary artery stenosis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Myocardial infarction | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Myocarditis | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Sinus tachycardia | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Endocrine disorders | ||||
| Adrenal insufficiency | 4/429 (0.9%) | 4 | 0/425 (0%) | 0 |
| Adrenocorticotropic hormone deficiency | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Hyperthyroidism | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Hypophysitis | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Hypothyroidism | 1/429 (0.2%) | 1 | 2/425 (0.5%) | 2 |
| Secondary adrenocortical insufficiency | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Eye disorders | ||||
| Vitreous floaters | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Gastrointestinal disorders | ||||
| Abdominal adhesions | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Abdominal pain | 2/429 (0.5%) | 2 | 1/425 (0.2%) | 1 |
| Abdominal wall haematoma | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Anal inflammation | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Ascites | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Colitis | 3/429 (0.7%) | 3 | 0/425 (0%) | 0 |
| Diarrhoea | 12/429 (2.8%) | 12 | 4/425 (0.9%) | 4 |
| Duodenal perforation | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Enteritis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Enterocolitis | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Enterocolitis haemorrhagic | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Gastric haemorrhage | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Gastroduodenitis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Gastrointestinal angiodysplasia | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Gastrointestinal haemorrhage | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Gastrointestinal perforation | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Gastrointestinal toxicity | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Gastrooesophageal reflux disease | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Haematochezia | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Haemorrhoids | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Ileus | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Mallory-Weiss syndrome | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Melaena | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Mouth haemorrhage | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Nausea | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Oesophagitis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Pancreatitis | 2/429 (0.5%) | 2 | 2/425 (0.5%) | 2 |
| Pneumatosis intestinalis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Small intestinal obstruction | 1/429 (0.2%) | 2 | 0/425 (0%) | 0 |
| Stomatitis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Upper gastrointestinal haemorrhage | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Vomiting | 2/429 (0.5%) | 2 | 2/425 (0.5%) | 2 |
| General disorders | ||||
| Asthenia | 3/429 (0.7%) | 3 | 4/425 (0.9%) | 4 |
| Chest pain | 2/429 (0.5%) | 2 | 1/425 (0.2%) | 1 |
| Condition aggravated | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Death | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Fatigue | 0/429 (0%) | 0 | 3/425 (0.7%) | 3 |
| Gait disturbance | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| General physical health deterioration | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Malaise | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Mucosal inflammation | 1/429 (0.2%) | 1 | 2/425 (0.5%) | 2 |
| Non-cardiac chest pain | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 3 |
| Pyrexia | 3/429 (0.7%) | 3 | 1/425 (0.2%) | 1 |
| Strangulated hernia | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Sudden cardiac death | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Sudden death | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Hepatobiliary disorders | ||||
| Autoimmune hepatitis | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Cholangitis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Cholecystitis | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Cholecystitis acute | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Cholelithiasis | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Drug-induced liver injury | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Hepatic cirrhosis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Hepatic function abnormal | 5/429 (1.2%) | 5 | 0/425 (0%) | 0 |
| Hepatic pain | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Hepatitis | 3/429 (0.7%) | 3 | 0/425 (0%) | 0 |
| Hepatitis fulminant | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Hepatocellular injury | 3/429 (0.7%) | 3 | 1/425 (0.2%) | 1 |
| Hepatotoxicity | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Immune-mediated hepatitis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Jaundice cholestatic | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Immune system disorders | ||||
| Anaphylactic reaction | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Contrast media allergy | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Contrast media reaction | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Hypersensitivity | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Infections and infestations | ||||
| Acute hepatitis C | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Anal abscess | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Appendicitis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Bacterial sepsis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Bronchitis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Cellulitis | 2/429 (0.5%) | 2 | 1/425 (0.2%) | 1 |
| Clostridium difficile infection | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Colonic abscess | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Device related infection | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Extrapulmonary tuberculosis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Gastroenteritis | 3/429 (0.7%) | 3 | 1/425 (0.2%) | 1 |
| Herpes zoster | 2/429 (0.5%) | 2 | 1/425 (0.2%) | 1 |
| Infection | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Influenza | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Klebsiella infection | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Labyrinthitis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Lower respiratory tract infection | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Lung infection | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Necrotising fasciitis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Oral fungal infection | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Osteomyelitis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Pancreas infection | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Perineal abscess | 0/429 (0%) | 0 | 1/425 (0.2%) | 2 |
| Periodontitis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Peritonitis | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Peritonsillar abscess | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Pneumonia | 4/429 (0.9%) | 4 | 10/425 (2.4%) | 12 |
| Sepsis | 1/429 (0.2%) | 1 | 2/425 (0.5%) | 3 |
| Skin infection | 0/429 (0%) | 0 | 1/425 (0.2%) | 2 |
| Upper respiratory tract infection | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Urinary tract infection | 3/429 (0.7%) | 4 | 3/425 (0.7%) | 3 |
| Injury, poisoning and procedural complications | ||||
| Carbon monoxide poisoning | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Comminuted fracture | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Femur fracture | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Fibula fracture | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Head injury | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Humerus fracture | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Incisional hernia | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Multiple fractures | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Pelvic fracture | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Postoperative respiratory failure | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Radiation necrosis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Rib fracture | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Tendon rupture | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Thoracic vertebral fracture | 1/429 (0.2%) | 2 | 0/425 (0%) | 0 |
| Tibia fracture | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Traumatic haemothorax | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Wound dehiscence | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Investigations | ||||
| Alanine aminotransferase increased | 6/429 (1.4%) | 6 | 0/425 (0%) | 0 |
| Aspartate aminotransferase increased | 5/429 (1.2%) | 5 | 0/425 (0%) | 0 |
| Blood bilirubin increased | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Blood creatine phosphokinase increased | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Blood electrolytes abnormal | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Blood pressure decreased | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Hepatic enzyme increased | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Liver function test increased | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Platelet count decreased | 0/429 (0%) | 0 | 3/425 (0.7%) | 3 |
| Transaminases increased | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Dehydration | 6/429 (1.4%) | 7 | 5/425 (1.2%) | 5 |
| Diabetes mellitus | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Diabetic ketoacidosis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Electrolyte imbalance | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Failure to thrive | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Gout | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Hypercalcaemia | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Hyperglycaemia | 3/429 (0.7%) | 3 | 0/425 (0%) | 0 |
| Hyperkalaemia | 1/429 (0.2%) | 2 | 1/425 (0.2%) | 1 |
| Hypoglycaemia | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Hypokalaemia | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Hyponatraemia | 2/429 (0.5%) | 2 | 5/425 (1.2%) | 5 |
| Hypophosphataemia | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Ketoacidosis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Metabolic acidosis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Arthritis | 1/429 (0.2%) | 2 | 0/425 (0%) | 0 |
| Back pain | 2/429 (0.5%) | 2 | 1/425 (0.2%) | 1 |
| Bone pain | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Muscular weakness | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Musculoskeletal chest pain | 2/429 (0.5%) | 2 | 1/425 (0.2%) | 1 |
| Musculoskeletal pain | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Myalgia | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Myositis | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Neck pain | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Pathological fracture | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Polymyalgia rheumatica | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Cancer pain | 1/429 (0.2%) | 1 | 2/425 (0.5%) | 2 |
| Colon cancer | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Endometrial cancer | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Invasive ductal breast carcinoma | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Malignant neoplasm progression | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Paraneoplastic syndrome | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Plasma cell myeloma | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Squamous cell carcinoma | 0/429 (0%) | 0 | 1/425 (0.2%) | 3 |
| Tumour pain | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Nervous system disorders | ||||
| Aphasia | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Cerebellar infarction | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Cerebral infarction | 2/429 (0.5%) | 2 | 1/425 (0.2%) | 1 |
| Cerebrovascular accident | 4/429 (0.9%) | 4 | 1/425 (0.2%) | 1 |
| Epilepsy | 0/429 (0%) | 0 | 1/425 (0.2%) | 2 |
| Facial paresis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Haemorrhage intracranial | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Headache | 3/429 (0.7%) | 4 | 1/425 (0.2%) | 1 |
| Myasthenia gravis | 4/429 (0.9%) | 4 | 0/425 (0%) | 0 |
| Pachymeningitis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Presyncope | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Spinal cord compression | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Transient ischaemic attack | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Psychiatric disorders | ||||
| Dependence | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Suicide attempt | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Renal and urinary disorders | ||||
| Acute kidney injury | 7/429 (1.6%) | 8 | 3/425 (0.7%) | 3 |
| Calculus urinary | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Chronic kidney disease | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Haematuria | 1/429 (0.2%) | 1 | 2/425 (0.5%) | 2 |
| Nephritis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Nephropathy toxic | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Proteinuria | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Renal colic | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Renal failure | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Renal haemorrhage | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Renal impairment | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Tubulointerstitial nephritis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Ureterolithiasis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Chronic obstructive pulmonary disease | 2/429 (0.5%) | 2 | 0/425 (0%) | 0 |
| Dyspnoea | 3/429 (0.7%) | 3 | 2/425 (0.5%) | 2 |
| Dyspnoea exertional | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Epiglottic cyst | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Haemoptysis | 0/429 (0%) | 0 | 2/425 (0.5%) | 2 |
| Hypoxia | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Interstitial lung disease | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Pleural effusion | 2/429 (0.5%) | 2 | 1/425 (0.2%) | 1 |
| Pneumonia aspiration | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Pneumonitis | 5/429 (1.2%) | 5 | 0/425 (0%) | 0 |
| Pulmonary artery thrombosis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Pulmonary embolism | 4/429 (0.9%) | 4 | 7/425 (1.6%) | 7 |
| Pulmonary haemorrhage | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Pulmonary thrombosis | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Respiratory failure | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Skin and subcutaneous tissue disorders | ||||
| Drug eruption | 1/429 (0.2%) | 1 | 1/425 (0.2%) | 1 |
| Palmar-plantar erythrodysaesthesia syndrome | 2/429 (0.5%) | 2 | 1/425 (0.2%) | 1 |
| Rash maculo-papular | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Skin ulcer | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Angioedema | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Vascular disorders | ||||
| Hypertension | 2/429 (0.5%) | 2 | 2/425 (0.5%) | 2 |
| Hypertensive crisis | 0/429 (0%) | 0 | 1/425 (0.2%) | 1 |
| Peripheral artery occlusion | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
| Venous thrombosis limb | 1/429 (0.2%) | 1 | 0/425 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
| Pembrolizumab + Axitinib | Sunitinib | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 417/429 (97.2%) | 415/425 (97.6%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 32/429 (7.5%) | 34 | 97/425 (22.8%) | 152 |
| Leukopenia | 6/429 (1.4%) | 11 | 41/425 (9.6%) | 79 |
| Neutropenia | 8/429 (1.9%) | 11 | 82/425 (19.3%) | 152 |
| Thrombocytopenia | 11/429 (2.6%) | 13 | 95/425 (22.4%) | 164 |
| Endocrine disorders | ||||
| Hyperthyroidism | 53/429 (12.4%) | 58 | 16/425 (3.8%) | 18 |
| Hypothyroidism | 152/429 (35.4%) | 177 | 133/425 (31.3%) | 172 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 48/429 (11.2%) | 64 | 29/425 (6.8%) | 32 |
| Abdominal pain upper | 26/429 (6.1%) | 35 | 26/425 (6.1%) | 31 |
| Constipation | 89/429 (20.7%) | 107 | 62/425 (14.6%) | 70 |
| Diarrhoea | 231/429 (53.8%) | 496 | 191/425 (44.9%) | 380 |
| Dry mouth | 25/429 (5.8%) | 27 | 25/425 (5.9%) | 26 |
| Dyspepsia | 22/429 (5.1%) | 26 | 62/425 (14.6%) | 73 |
| Gastrooesophageal reflux disease | 18/429 (4.2%) | 18 | 48/425 (11.3%) | 60 |
| Nausea | 119/429 (27.7%) | 174 | 134/425 (31.5%) | 205 |
| Stomatitis | 67/429 (15.6%) | 86 | 88/425 (20.7%) | 110 |
| Vomiting | 64/429 (14.9%) | 97 | 78/425 (18.4%) | 125 |
| General disorders | ||||
| Asthenia | 62/429 (14.5%) | 85 | 60/425 (14.1%) | 77 |
| Fatigue | 165/429 (38.5%) | 208 | 158/425 (37.2%) | 211 |
| Mucosal inflammation | 56/429 (13.1%) | 77 | 92/425 (21.6%) | 143 |
| Oedema peripheral | 28/429 (6.5%) | 29 | 34/425 (8%) | 43 |
| Pyrexia | 53/429 (12.4%) | 65 | 42/425 (9.9%) | 46 |
| Infections and infestations | ||||
| Nasopharyngitis | 33/429 (7.7%) | 41 | 15/425 (3.5%) | 23 |
| Upper respiratory tract infection | 27/429 (6.3%) | 31 | 20/425 (4.7%) | 20 |
| Urinary tract infection | 37/429 (8.6%) | 54 | 25/425 (5.9%) | 28 |
| Investigations | ||||
| Alanine aminotransferase increased | 110/429 (25.6%) | 158 | 64/425 (15.1%) | 81 |
| Aspartate aminotransferase increased | 108/429 (25.2%) | 163 | 69/425 (16.2%) | 95 |
| Blood alkaline phosphatase increased | 27/429 (6.3%) | 32 | 19/425 (4.5%) | 21 |
| Blood bilirubin increased | 28/429 (6.5%) | 45 | 24/425 (5.6%) | 39 |
| Blood creatinine increased | 48/429 (11.2%) | 79 | 51/425 (12%) | 72 |
| Blood thyroid stimulating hormone increased | 23/429 (5.4%) | 25 | 22/425 (5.2%) | 28 |
| Neutrophil count decreased | 4/429 (0.9%) | 6 | 50/425 (11.8%) | 109 |
| Platelet count decreased | 16/429 (3.7%) | 21 | 76/425 (17.9%) | 148 |
| Weight decreased | 76/429 (17.7%) | 86 | 47/425 (11.1%) | 54 |
| White blood cell count decreased | 2/429 (0.5%) | 2 | 43/425 (10.1%) | 97 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 126/429 (29.4%) | 173 | 125/425 (29.4%) | 156 |
| Hyperglycaemia | 31/429 (7.2%) | 53 | 20/425 (4.7%) | 26 |
| Hyperkalaemia | 30/429 (7%) | 62 | 14/425 (3.3%) | 16 |
| Hypophosphataemia | 9/429 (2.1%) | 20 | 36/425 (8.5%) | 57 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 78/429 (18.2%) | 95 | 25/425 (5.9%) | 33 |
| Back pain | 55/429 (12.8%) | 64 | 42/425 (9.9%) | 45 |
| Musculoskeletal pain | 26/429 (6.1%) | 29 | 18/425 (4.2%) | 19 |
| Myalgia | 36/429 (8.4%) | 41 | 19/425 (4.5%) | 23 |
| Pain in extremity | 51/429 (11.9%) | 69 | 42/425 (9.9%) | 48 |
| Nervous system disorders | ||||
| Dizziness | 22/429 (5.1%) | 25 | 28/425 (6.6%) | 31 |
| Dysgeusia | 47/429 (11%) | 52 | 131/425 (30.8%) | 185 |
| Headache | 67/429 (15.6%) | 91 | 68/425 (16%) | 87 |
| Psychiatric disorders | ||||
| Insomnia | 36/429 (8.4%) | 40 | 39/425 (9.2%) | 39 |
| Renal and urinary disorders | ||||
| Haematuria | 22/429 (5.1%) | 23 | 20/425 (4.7%) | 27 |
| Proteinuria | 74/429 (17.2%) | 104 | 47/425 (11.1%) | 77 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 91/429 (21.2%) | 108 | 58/425 (13.6%) | 66 |
| Dysphonia | 109/429 (25.4%) | 126 | 14/425 (3.3%) | 18 |
| Dyspnoea | 69/429 (16.1%) | 80 | 44/425 (10.4%) | 49 |
| Epistaxis | 27/429 (6.3%) | 30 | 40/425 (9.4%) | 45 |
| Oropharyngeal pain | 28/429 (6.5%) | 31 | 19/425 (4.5%) | 27 |
| Skin and subcutaneous tissue disorders | ||||
| Dry skin | 29/429 (6.8%) | 31 | 39/425 (9.2%) | 47 |
| Palmar-plantar erythrodysaesthesia syndrome | 118/429 (27.5%) | 140 | 169/425 (39.8%) | 235 |
| Pruritus | 65/429 (15.2%) | 78 | 25/425 (5.9%) | 33 |
| Rash | 61/429 (14.2%) | 84 | 47/425 (11.1%) | 60 |
| Vascular disorders | ||||
| Hypertension | 189/429 (44.1%) | 317 | 192/425 (45.2%) | 278 |
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 |
- 3475-426
- 2016-000588-17
- 163460
- MK-3475-426
- KEYNOTE-426