A Study of Nivolumab Combined With Cabozantinib Compared to Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 9ER)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT03141177

Recruitment Status : Active, not recruiting

First Posted : May 4, 2017

Results First Posted : April 26, 2022

Last Update Posted : January 17, 2024

View this study on the modernized ClinicalTrials.gov

Sponsor:

Collaborators:

Exelixis

Ono Pharmaceutical Co. Ltd

Information provided by (Responsible Party):

Bristol-Myers Squibb

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Renal Cell Carcinoma
Interventions	Biological: Nivolumab Drug: Cabozantinib Drug: Sunitinib Biological: Ipilimumab
Enrollment	701

Participant Flow

Recruitment Details
Pre-assignment Details	701 participants randomized and 690 treated.


Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description	Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Period Title: Overall Study
Started ^[1]	323	50	328
Treated ^[2]	320	50	320
Completed ^[3]	242	34	210
Not Completed	81	16	118
Reason Not Completed
Death	62	13	84
Participant withdrew consent	9	2	13
Not reported	1	0	1
Lost to Follow-up	2	1	1
Other reasons	4	0	11
Participants did not start treatment period	3	0	8
[1] Started=Randomized [2] Treated=Started treatment period [3] Completed=Continuing in the Study

Baseline Characteristics

Arm/Group Title		Treatment A	Treatment B	Treatment C	Total
Arm/Group Description		Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...	Total of all reporting groups
Arm/Group Description		Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle	Total of all reporting groups
Overall Number of Baseline Participants		323	50	328	701
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	323 participants	50 participants	328 participants	701 participants
		61.4 (10.2)	60.3 (9.5)	60.4 (10.6)	60.9 (10.4)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	323 participants	50 participants	328 participants	701 participants
	Female	74 22.9%	16 32.0%	96 29.3%	186 26.5%
	Male	249 77.1%	34 68.0%	232 70.7%	515 73.5%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	323 participants	50 participants	328 participants	701 participants
	Hispanic or Latino	38 11.8%	13 26.0%	39 11.9%	90 12.8%
	Not Hispanic or Latino	149 46.1%	19 38.0%	151 46.0%	319 45.5%
	Unknown or Not Reported	136 42.1%	18 36.0%	138 42.1%	292 41.7%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	323 participants	50 participants	328 participants	701 participants
	American Indian or Alaska Native	3 0.9%	0 0.0%	2 0.6%	5 0.7%
	Asian	26 8.0%	0 0.0%	25 7.6%	51 7.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 0.3%	0 0.0%	4 1.2%	5 0.7%
	White	267 82.7%	43 86.0%	266 81.1%	576 82.2%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	26 8.0%	7 14.0%	31 9.5%	64 9.1%

Outcome Measures

1.Primary Outcome


Title	Progression Free Survival (PFS)
Description	PFS is defined as the time from date of randomization to the first doc...
Description	PFS is defined as the time from date of randomization to the first documented tumor progression date or death due to any cause, whichever occurs first based on BICR assessment using RECIST v1.1. Participants who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment on or prior to initiation of subsequent anti-cancer therapy. Progressive disease (PD); 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study
Time Frame	From randomization date to date of first documented tumor progression or death, whichever occurs first (Up to 31 months)

Outcome Measure Data

Analysis Population Description

All Randomized Participants of treatment A and treatment C


Arm/Group Title	Treatment A	Treatment C
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W +...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Overall Number of Participants Analyzed	323	328
Median (95% Confidence Interval) Unit of Measure: Months
	16.59 (12.45 to 24.94)	8.31 (6.97 to 9.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Treatment A over Treatment C

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95% 0.41 to 0.64
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Overall Survival (OS)
Description	Overall Survival is defined as the time between the date of randomizat...
Description	Overall Survival is defined as the time between the date of randomization and the date of death due to any cause. For participants that are alive, their survival time will be censored at the date of last contact date (or "last known alive date").
Time Frame	From randomization date to death date (Up to 31 months)

Outcome Measure Data

Analysis Population Description

All Randomized Participants of treatment A and treatment C


Arm/Group Title	Treatment A	Treatment C
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W +...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Overall Number of Participants Analyzed	323	328
Median (95% Confidence Interval) Unit of Measure: Months
	NA ^[1] (NA to NA)	NA ^[1] (22.6 to NA)

[1]

Insufficient number of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Treatment A over Treatment C

Statistical Test of Hypothesis	P-Value	0.0010
	Comments	[Not Specified]
	Method	Stratified Log-Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 98.89% 0.40 to 0.89
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Objective Response Rate (ORR)
Description	Objective Response Rate (ORR) is defined as the percentage of randomiz...
Description	Objective Response Rate (ORR) is defined as the percentage of randomized participants who achieve a best response of confirmed complete response (CR) or confirmed partial response (PR) based on BICR assessments (using RECIST v1.1 criteria) divided by the number of all randomized participants. Complete response (CR): Disappearance of all target lesions. Partial response (PR): 30% decrease in the sum of diameters of target lesions.
Time Frame	Up to 31 Months

Outcome Measure Data

Analysis Population Description

All Randomized Participants


Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Overall Number of Participants Analyzed	323	50	328
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	55.7 (50.1 to 61.2)	44.0 (30.0 to 58.7)	27.1 (22.4 to 32.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Treatment A over Treatment C

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.52
	Confidence Interval	(2-Sided) 95% 2.51 to 4.95
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment C
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Treatment A - Treatment C

Method of Estimation	Estimation Parameter	Difference of Objective Response Rates
	Estimated Value	28.6
	Confidence Interval	(2-Sided) 95% 21.7 to 35.6
	Estimation Comments	Strata adjusted difference in objective response rate (Nivolumab+Cabozantinib - Sunitinib) based on DerSimonian and Laird.

4.Secondary Outcome


Title	Number of Participants Experiencing Adverse Events (AEs)
Description	Number of participants experiencing various types of any grade adverse...
Description	Number of participants experiencing various types of any grade adverse events (AEs) during the specified time frame.
Time Frame	From first dose to 100 days following last dose (Up to 32 Months)

Outcome Measure Data

Analysis Population Description

All Treated Participants


Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Overall Number of Participants Analyzed	320	50	320
Measure Type: Count of Participants Unit of Measure: Participants
	319 99.7%	50 100.0%	317 99.1%

5.Secondary Outcome


Title	Number of Participants Experiencing Serious Adverse Events (SAEs)
Description	Number of participants experiencing various types of any grade serious...
Description	Number of participants experiencing various types of any grade serious adverse events (SAEs) during the specified time frame.
Time Frame	From first to dose to 100 days following last dose (Up to 32 months)

Outcome Measure Data

Analysis Population Description

All Treated Participants


Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Overall Number of Participants Analyzed	320	50	320
Measure Type: Count of Participants Unit of Measure: Participants
	160 50.0%	28 56.0%	144 45.0%

6.Secondary Outcome


Title	Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation
Description	Number of participants experiencing various types of any grade adverse...
Description	Number of participants experiencing various types of any grade adverse events (AEs) leading to discontinuation during the specified time frame.
Time Frame	From first dose to 30 days following last dose (Up to 30 months)

Outcome Measure Data

Analysis Population Description

All Treated Participants


Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Overall Number of Participants Analyzed	320	50	320
Measure Type: Count of Participants Unit of Measure: Participants
	63 19.7%	15 30.0%	54 16.9%

7.Secondary Outcome


Title	Number of Deaths
Description	Number of deaths due to any cause during the specified time frame.
Description	Number of deaths due to any cause during the specified time frame.
Time Frame	From first dose to (up to 31 months) following first dose

Outcome Measure Data

Analysis Population Description

All Treated Participants


Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description:	Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Overall Number of Participants Analyzed	320	50	320
Measure Type: Count of Participants Unit of Measure: Participants
	67 20.9%	14 28.0%	99 30.9%

8.Secondary Outcome


Title	Number of Participants With Laboratory Abnormalities
Description	Number of participants experiencing laboratory abnormalities in hemato...
Description	Number of participants experiencing laboratory abnormalities in hematology, serum chemistry and electrolytes with grade 3 or higher during the specified time frame.
Time Frame	From first dose to 30 days following last dose (Up to 30 Months)

Outcome Measure Data

Analysis Population Description

All Treated Participants


Arm/Group Title		Treatment A	Treatment B	Treatment C
Arm/Group Description:		Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description:		Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Overall Number of Participants Analyzed		320	50	320
Measure Type: Count of Participants Unit of Measure: Participants
Hemoglobin: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Hemoglobin: Any grade		235 74.1%	35 71.4%	256 82.3%
Hemoglobin: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Hemoglobin: Grade 3-4		9 2.8%	5 10.2%	15 4.8%
Platelet Count: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Platelet Count: Any grade		137 43.2%	27 55.1%	216 69.5%
Platelet Count: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Platelet Count: Grade 3-4		1 0.3%	0 0.0%	30 9.6%
Leukocytes: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Leukocytes: Any grade		121 38.2%	26 53.1%	207 66.6%
Leukocytes: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Leukocytes: Grade 3-4		1 0.3%	0 0.0%	16 5.1%
Lymphocytes: Any grade	Number Analyzed	231 participants	36 participants	231 participants
Lymphocytes: Any grade		107 46.3%	22 61.1%	118 51.1%
Lymphocytes: Grade 3-4	Number Analyzed	231 participants	36 participants	231 participants
Lymphocytes: Grade 3-4		16 6.9%	4 11.1%	24 10.4%
Neutrophil: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Neutrophil: Any grade		115 36.3%	22 44.9%	209 67.2%
Neutrophil: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Neutrophil: Grade 3-4		10 3.2%	2 4.1%	36 11.6%
Alkaline Phosphatase: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Alkaline Phosphatase: Any grade		194 61.2%	35 71.4%	167 53.7%
Alkaline Phosphatase: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Alkaline Phosphatase: Grade 3-4		12 3.8%	6 12.2%	6 1.9%
Aspartate Aminotransferase (AST): Any grade	Number Analyzed	317 participants	49 participants	311 participants
Aspartate Aminotransferase (AST): Any grade		260 82.0%	43 87.8%	235 75.6%
Aspartate Aminotransferase (AST): Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Aspartate Aminotransferase (AST): Grade 3-4		25 7.9%	19 38.8%	8 2.6%
Alanine Aminotransferase (ALT): Any grade	Number Analyzed	317 participants	49 participants	311 participants
Alanine Aminotransferase (ALT): Any grade		268 84.5%	46 93.9%	133 42.8%
Alanine Aminotransferase (ALT): Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Alanine Aminotransferase (ALT): Grade 3-4		31 9.8%	24 49.0%	11 3.5%
Bilirubin: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Bilirubin: Any grade		57 18.0%	17 34.7%	72 23.2%
Bilirubin: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Bilirubin: Grade 3-4		3 0.9%	3 6.1%	3 1.0%
Creatinine: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Creatinine: Any grade		221 69.7%	34 69.4%	211 67.8%
Creatinine: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Creatinine: Grade 3-4		4 1.3%	0 0.0%	2 0.6%
Amylase: Any grade	Number Analyzed	295 participants	46 participants	283 participants
Amylase: Any grade		48 16.3%	28 60.9%	41 14.5%
Amylase: Grade 3-4	Number Analyzed	295 participants	46 participants	283 participants
Amylase: Grade 3-4		30 10.2%	10 21.7%	17 6.0%
Lipase: Any grade	Number Analyzed	317 participants	48 participants	306 participants
Lipase: Any grade		36 11.4%	27 56.3%	42 13.7%
Lipase: Grade 3-4	Number Analyzed	317 participants	48 participants	306 participants
Lipase: Grade 3-4		46 14.5%	20 41.7%	41 13.4%
Hypernatremia: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Hypernatremia: Any grade		33 10.4%	7 14.3%	24 7.7%
Hypernatremia: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Hypernatremia: Grade 3-4		0 0.0%	0 0.0%	0 0.0%
Hyponatremia: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Hyponatremia: Any grade		160 50.5%	31 63.3%	140 45.0%
Hyponatremia: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Hyponatremia: Grade 3-4		36 11.4%	9 18.4%	41 13.2%
Hyperkalemia: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Hyperkalemia: Any grade		136 42.9%	27 55.1%	100 32.2%
Hyperkalemia: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Hyperkalemia: Grade 3-4		16 5.0%	2 4.1%	3 1.0%
Hypokalemia: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Hypokalemia: Any grade		64 20.2%	8 16.3%	37 11.9%
Hypokalemia: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Hypokalemia: Grade 3-4		11 3.5%	0 0.0%	6 1.9%
Hypercalcemia: Any grade	Number Analyzed	315 participants	48 participants	310 participants
Hypercalcemia: Any grade		40 12.7%	9 18.8%	58 18.7%
Hypercalcemia: Grade 3-4	Number Analyzed	315 participants	48 participants	310 participants
Hypercalcemia: Grade 3-4		1 0.3%	0 0.0%	4 1.3%
Hypocalcemia: Any grade	Number Analyzed	315 participants	48 participants	310 participants
Hypocalcemia: Any grade		174 55.2%	25 52.1%	77 24.8%
Hypocalcemia: Grade 3-4	Number Analyzed	315 participants	48 participants	310 participants
Hypocalcemia: Grade 3-4		6 1.9%	2 4.2%	2 0.6%
Hypermagnesemia: Any grade	Number Analyzed	316 participants	49 participants	309 participants
Hypermagnesemia: Any grade		42 13.3%	9 18.4%	29 9.4%
Hypermagnesemia: Grade 3-4	Number Analyzed	316 participants	49 participants	309 participants
Hypermagnesemia: Grade 3-4		12 3.8%	4 8.2%	7 2.3%
Hypomagnesemia: Any grade	Number Analyzed	316 participants	49 participants	309 participants
Hypomagnesemia: Any grade		155 49.1%	18 36.7%	90 29.1%
Hypomagnesemia: Grade 3-4	Number Analyzed	316 participants	49 participants	309 participants
Hypomagnesemia: Grade 3-4		4 1.3%	1 2.0%	1 0.3%
Hyperphosphatemia: Any grade	Number Analyzed	316 participants	49 participants	309 participants
Hyperphosphatemia: Any grade		0 0.0%	0 0.0%	0 0.0%
Hyperphosphatemia: Grade 3-4	Number Analyzed	316 participants	49 participants	309 participants
Hyperphosphatemia: Grade 3-4		0 0.0%	0 0.0%	0 0.0%
Hypophosphatemia: Any grade	Number Analyzed	316 participants	49 participants	309 participants
Hypophosphatemia: Any grade		226 71.5%	34 69.4%	154 49.8%
Hypophosphatemia: Grade 3-4	Number Analyzed	316 participants	49 participants	309 participants
Hypophosphatemia: Grade 3-4		88 27.8%	12 24.5%	31 10.0%
Hyperglycemia: Any grade	Number Analyzed	203 participants	37 participants	196 participants
Hyperglycemia: Any grade		135 66.5%	29 78.4%	139 70.9%
Hyperglycemia: Grade 3-4	Number Analyzed	203 participants	37 participants	196 participants
Hyperglycemia: Grade 3-4		8 3.9%	2 5.4%	4 2.0%
Hypoglycemia: Any grade	Number Analyzed	308 participants	49 participants	295 participants
Hypoglycemia: Any grade		72 23.4%	10 20.4%	41 13.9%
Hypoglycemia: Grade 3-4	Number Analyzed	308 participants	49 participants	295 participants
Hypoglycemia: Grade 3-4		2 0.6%	1 2.0%	1 0.3%

9.Secondary Outcome


Title	Number of Participants With Laboratory Values Grade Shifting From Baseline
Description	Number of participants experiencing worsening shift from baseline in a...
Description	Number of participants experiencing worsening shift from baseline in any grade and grade 3-4 of laboratory values during the specified time frame.
Time Frame	From first dose to 30 days following last dose (Up to 30 Months)

Outcome Measure Data

Analysis Population Description

All Treated Participants


Arm/Group Title		Treatment A	Treatment B	Treatment C
Arm/Group Description:		Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description:		Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
Overall Number of Participants Analyzed		320	50	320
Measure Type: Count of Participants Unit of Measure: Participants
Hemoglobin: Any grade	Number Analyzed	316 participants	49 participants	251 participants
Hemoglobin: Any grade		117 37.0%	23 46.9%	190 75.7%
Hemoglobin: Grade 3-4	Number Analyzed	316 participants	49 participants	251 participants
Hemoglobin: Grade 3-4		8 2.5%	5 10.2%	15 6.0%
Platelet Count: Any grade	Number Analyzed	316 participants	48 participants	310 participants
Platelet Count: Any grade		129 40.8%	24 50.0%	216 69.7%
Platelet Count: Grade 3-4	Number Analyzed	316 participants	48 participants	310 participants
Platelet Count: Grade 3-4		2 0.6%	0 0.0%	30 9.7%
Leukocytes: Any grade	Number Analyzed	316 participants	49 participants	311 participants
Leukocytes: Any grade		116 36.7%	26 53.1%	206 66.2%
Leukocytes: Grade 3-4	Number Analyzed	316 participants	49 participants	311 participants
Leukocytes: Grade 3-4		1 0.3%	0 0.0%	16 5.1%
Lymphocytes: Any grade	Number Analyzed	228 participants	36 participants	225 participants
Lymphocytes: Any grade		95 41.7%	20 55.6%	102 45.3%
Lymphocytes: Grade 3-4	Number Analyzed	228 participants	36 participants	225 participants
Lymphocytes: Grade 3-4		15 6.6%	4 11.1%	23 10.2%
Neutrophil: Any grade	Number Analyzed	316 participants	49 participants	311 participants
Neutrophil: Any grade		112 35.4%	22 44.9%	209 67.2%
Neutrophil: Grade 3-4	Number Analyzed	316 participants	49 participants	311 participants
Neutrophil: Grade 3-4		10 3.2%	2 4.1%	36 11.6%
Alkaline Phosphatase: Any grade	Number Analyzed	317 participants	49 participants	310 participants
Alkaline Phosphatase: Any grade		131 41.3%	31 63.3%	115 37.1%
Alkaline Phosphatase: Grade 3-4	Number Analyzed	317 participants	49 participants	310 participants
Alkaline Phosphatase: Grade 3-4		9 2.8%	6 12.2%	5 1.6%
Aspartate Aminotransferase (AST): Any grade	Number Analyzed	317 participants	49 participants	310 participants
Aspartate Aminotransferase (AST): Any grade		245 77.3%	42 85.7%	177 57.1%
Aspartate Aminotransferase (AST): Grade 3-4	Number Analyzed	317 participants	49 participants	310 participants
Aspartate Aminotransferase (AST): Grade 3-4		25 7.9%	19 38.8%	8 2.6%
Alanine Aminotransferase (ALT): Any grade	Number Analyzed	316 participants	49 participants	310 participants
Alanine Aminotransferase (ALT): Any grade		249 78.8%	43 87.8%	121 39.0%
Alanine Aminotransferase (ALT) Grade 3-4	Number Analyzed	316 participants	49 participants	310 participants
Alanine Aminotransferase (ALT) Grade 3-4		31 9.8%	24 49.0%	11 3.5%
Bilirubin: Any grade	Number Analyzed	316 participants	49 participants	309 participants
Bilirubin: Any grade		55 17.4%	17 34.7%	68 22.0%
Bilirubin: Grade 3-4	Number Analyzed	316 participants	49 participants	309 participants
Bilirubin: Grade 3-4		3 0.9%	3 6.1%	3 1.0%
Creatinine: Any grade	Number Analyzed	317 participants	49 participants	311 participants
Creatinine: Any grade		123 38.8%	22 44.9%	132 42.4%
Creatinine: Grade 3-4	Number Analyzed	317 participants	49 participants	311 participants
Creatinine: Grade 3-4		4 1.3%	0 0.0%	2 0.6%
Amylase: Any grade	Number Analyzed	285 participants	46 participants	277 participants
Amylase: Any grade		117 41.1%	26 56.5%	77 27.8%
Amylase: Grade 3-4	Number Analyzed	285 participants	46 participants	277 participants
Amylase: Grade 3-4		28 9.8%	10 21.7%	16 5.8%
Lipase: Any grade	Number Analyzed	308 participants	47 participants	300 participants
Lipase: Any grade		127 41.2%	27 57.4%	114 38.0%
Lipase: Grade 3-4	Number Analyzed	308 participants	47 participants	300 participants
Lipase: Grade 3-4		42 13.6%	20 42.6%	40 13.3%
Hypernatremia: Any grade	Number Analyzed	317 participants	49 participants	310 participants
Hypernatremia: Any grade		33 10.4%	7 14.3%	24 7.7%
Hypernatremia: Grade 3-4	Number Analyzed	317 participants	49 participants	310 participants
Hypernatremia: Grade 3-4		0 0.0%	0 0.0%	0 0.0%
Hyponatremia: Any grade	Number Analyzed	317 participants	49 participants	310 participants
Hyponatremia: Any grade		136 42.9%	30 61.2%	111 35.8%
Hyponatremia: Grade 3-4	Number Analyzed	317 participants	49 participants	310 participants
Hyponatremia: Grade 3-4		34 10.7%	8 16.3%	37 11.9%
Hyperkalemia: Any grade	Number Analyzed	317 participants	49 participants	309 participants
Hyperkalemia: Any grade		111 35.0%	25 51.0%	82 26.5%
Hyperkalemia: Grade 3-4	Number Analyzed	317 participants	49 participants	309 participants
Hyperkalemia: Grade 3-4		15 4.7%	2 4.1%	3 1.0%
Hypokalemia: Any grade	Number Analyzed	317 participants	49 participants	309 participants
Hypokalemia: Any grade		61 19.2%	8 16.3%	35 11.3%
Hypokalemia: Grade 3-4	Number Analyzed	317 participants	49 participants	309 participants
Hypokalemia: Grade 3-4		10 3.2%	0 0.0%	5 1.6%
Hypercalcemia: Any grade	Number Analyzed	314 participants	48 participants	309 participants
Hypercalcemia: Any grade		30 9.6%	7 14.6%	46 14.9%
Hypercalcemia: Grade 3-4	Number Analyzed	314 participants	48 participants	309 participants
Hypercalcemia: Grade 3-4		1 0.3%	0 0.0%	3 1.0%
Hypocalcemia: Any grade	Number Analyzed	314 participants	48 participants	309 participants
Hypocalcemia: Any grade		170 54.1%	25 52.1%	73 23.6%
Hypocalcemia: Grade 3-4	Number Analyzed	314 participants	48 participants	309 participants
Hypocalcemia: Grade 3-4		6 1.9%	2 4.2%	2 0.6%
Hypermagnesemia: Any grade	Number Analyzed	308 participants	49 participants	304 participants
Hypermagnesemia: Any grade		38 12.3%	9 18.4%	26 8.6%
Hypermagnesemia: Grade 3-4	Number Analyzed	308 participants	49 participants	304 participants
Hypermagnesemia: Grade 3-4		12 3.9%	4 8.2%	7 2.3%
Hypomagnesemia: Any grade	Number Analyzed	308 participants	49 participants	304 participants
Hypomagnesemia: Any grade		146 47.4%	16 32.7%	77 25.3%
Hypomagnesemia: Grade 3-4	Number Analyzed	308 participants	49 participants	304 participants
Hypomagnesemia: Grade 3-4		4 1.3%	1 2.0%	1 0.3%
Hyperphosphatemia: Any grade	Number Analyzed	307 participants	49 participants	307 participants
Hyperphosphatemia: Any grade		0 0.0%	0 0.0%	0 0.0%
Hyperphosphatemia: Grade 3-4	Number Analyzed	307 participants	49 participants	307 participants
Hyperphosphatemia: Grade 3-4		0 0.0%	0 0.0%	0 0.0%
Hypophosphatemia: Any grade	Number Analyzed	307 participants	49 participants	307 participants
Hypophosphatemia: Any grade		211 68.7%	33 67.3%	147 47.9%
Hypophosphatemia: Grade 3-4	Number Analyzed	307 participants	49 participants	307 participants
Hypophosphatemia: Grade 3-4		85 27.7%	12 24.5%	31 10.1%
Hyperglycemia: Any grade	Number Analyzed	170 participants	33 participants	173 participants
Hyperglycemia: Any grade		74 43.5%	17 51.5%	76 43.9%
Hyperglycemia: Grade 3-4	Number Analyzed	170 participants	33 participants	173 participants
Hyperglycemia: Grade 3-4		6 3.5%	2 6.1%	3 1.7%
Hypoglycemia: Any grade	Number Analyzed	262 participants	45 participants	270 participants
Hypoglycemia: Any grade		67 25.6%	9 20.0%	37 13.7%
Hypoglycemia: Grade 3-4	Number Analyzed	262 participants	45 participants	270 participants
Hypoglycemia: Grade 3-4		2 0.8%	1 2.2%	1 0.4%

Adverse Events

Time Frame	All cause mortality: From first visit to up to 31 months following first visit SAEs and AEs: From first dose to 100 days following last dose (up to 32 months)
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Treatment A	Treatment B	Treatment C
Arm/Group Description	Nivolumab 240 mg flat dose IV Q2W +...	Nivolumab 3 mg/kg IV Q3W (x4 doses)...	Sunitinib 50 mg PO QD for 4 weeks, ...
Arm/Group Description	Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Nivolumab 3 mg/kg IV Q3W (x4 doses) + Cabozantinib 40 mg PO QD + Ipilimumab 1 mg/kg IV Q3W (x4 doses) Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD	Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle
All-Cause Mortality
	Treatment A	Treatment B	Treatment C
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	67/320 (20.94%)	14/50 (28.00%)	99/320 (30.94%)
Serious Adverse Events Serious Adverse Events
	Treatment A	Treatment B	Treatment C
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	160/320 (50.00%)	28/50 (56.00%)	144/320 (45.00%)
Blood and lymphatic system disorders
Anaemia ^† 1	2/320 (0.63%)	1/50 (2.00%)	11/320 (3.44%)
Disseminated intravascular coagulation ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Febrile neutropenia ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Pancytopenia ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Thrombocytopenia ^† 1	0/320 (0.00%)	1/50 (2.00%)	3/320 (0.94%)
Cardiac disorders
Acute myocardial infarction ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Atrial fibrillation ^† 1	3/320 (0.94%)	0/50 (0.00%)	0/320 (0.00%)
Atrial tachycardia ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Atrioventricular block complete ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Bradycardia ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Cardiac arrest ^† 1	3/320 (0.94%)	0/50 (0.00%)	0/320 (0.00%)
Cardiac failure ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Cardiac failure acute ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Cardiac failure congestive ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Cardio-respiratory arrest ^† 1	2/320 (0.63%)	0/50 (0.00%)	2/320 (0.63%)
Intracardiac thrombus ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Myocardial infarction ^† 1	2/320 (0.63%)	1/50 (2.00%)	1/320 (0.31%)
Myocardial ischaemia ^† 1	1/320 (0.31%)	0/50 (0.00%)	2/320 (0.63%)
Myocarditis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Ear and labyrinth disorders
Vertigo ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Endocrine disorders
Adrenal haemorrhage ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Adrenal insufficiency ^† 1	6/320 (1.88%)	2/50 (4.00%)	0/320 (0.00%)
Adrenocorticotropic hormone deficiency ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Hyperthyroidism ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Hypophysitis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Hypothalamo-pituitary disorder ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Hypothyroidism ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Thyroiditis acute ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Eye disorders
Vision blurred ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Gastrointestinal disorders
Abdominal distension ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Abdominal hernia ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Abdominal pain ^† 1	3/320 (0.94%)	0/50 (0.00%)	4/320 (1.25%)
Anal fistula ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Colitis ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Colitis microscopic ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Colonic fistula ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Constipation ^† 1	0/320 (0.00%)	1/50 (2.00%)	1/320 (0.31%)
Diarrhoea ^† 1	15/320 (4.69%)	0/50 (0.00%)	0/320 (0.00%)
Dysphagia ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Enteritis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Epigastric discomfort ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Gastric haemorrhage ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Gastrointestinal haemorrhage ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Inguinal hernia ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Intestinal obstruction ^† 1	1/320 (0.31%)	1/50 (2.00%)	0/320 (0.00%)
Intestinal perforation ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Intussusception ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Large intestinal haemorrhage ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Large intestine perforation ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Lower gastrointestinal haemorrhage ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Nausea ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Obstruction gastric ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Oesophagitis ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Pancreatitis ^† 1	1/320 (0.31%)	1/50 (2.00%)	0/320 (0.00%)
Pancreatitis acute ^† 1	1/320 (0.31%)	1/50 (2.00%)	0/320 (0.00%)
Retroperitoneal haematoma ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Small intestinal obstruction ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Small intestinal perforation ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Stomatitis ^† 1	3/320 (0.94%)	0/50 (0.00%)	0/320 (0.00%)
Upper gastrointestinal haemorrhage ^† 1	1/320 (0.31%)	0/50 (0.00%)	2/320 (0.63%)
Vomiting ^† 1	5/320 (1.56%)	0/50 (0.00%)	2/320 (0.63%)
General disorders
Asthenia ^† 1	2/320 (0.63%)	1/50 (2.00%)	2/320 (0.63%)
Chills ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Condition aggravated ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Death ^† 1	1/320 (0.31%)	1/50 (2.00%)	2/320 (0.63%)
Face oedema ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Fatigue ^† 1	2/320 (0.63%)	0/50 (0.00%)	1/320 (0.31%)
General physical health deterioration ^† 1	2/320 (0.63%)	1/50 (2.00%)	1/320 (0.31%)
Hernia ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Inflammation ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Malaise ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Mucosal inflammation ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Necrosis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Pain ^† 1	2/320 (0.63%)	0/50 (0.00%)	6/320 (1.88%)
Pyrexia ^† 1	4/320 (1.25%)	0/50 (0.00%)	5/320 (1.56%)
Sudden death ^† 1	1/320 (0.31%)	0/50 (0.00%)	2/320 (0.63%)
Hepatobiliary disorders
Autoimmune hepatitis ^† 1	1/320 (0.31%)	1/50 (2.00%)	0/320 (0.00%)
Bile duct stone ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Cholangitis ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Cholecystitis ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Cholecystitis acute ^† 1	1/320 (0.31%)	1/50 (2.00%)	0/320 (0.00%)
Cholestasis ^† 1	1/320 (0.31%)	1/50 (2.00%)	0/320 (0.00%)
Drug-induced liver injury ^† 1	0/320 (0.00%)	1/50 (2.00%)	1/320 (0.31%)
Hepatic cirrhosis ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Hepatic failure ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Hepatic function abnormal ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Hepatitis ^† 1	2/320 (0.63%)	2/50 (4.00%)	0/320 (0.00%)
Hepatotoxicity ^† 1	2/320 (0.63%)	1/50 (2.00%)	1/320 (0.31%)
Hyperbilirubinaemia ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Immune-mediated hepatitis ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Jaundice ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Portal vein thrombosis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Immune system disorders
Anaphylactic reaction ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Infections and infestations
Abdominal sepsis ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Appendicitis perforated ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Bronchitis pneumococcal ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Campylobacter infection ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Cellulitis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Clostridium difficile colitis ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Clostridium difficile infection ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Cystitis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Dengue fever ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Diverticulitis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Encephalitis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Febrile infection ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Gastroenteritis viral ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Haematoma infection ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Herpes zoster ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Infection ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Infectious pleural effusion ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Large intestine infection ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Lower respiratory tract infection ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Lung abscess ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Otitis externa ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Pneumocystis jirovecii infection ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Pneumonia ^† 1	9/320 (2.81%)	4/50 (8.00%)	8/320 (2.50%)
Pneumonia necrotising ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Pulmonary sepsis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Pyelonephritis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Respiratory tract infection ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Sepsis ^† 1	4/320 (1.25%)	0/50 (0.00%)	0/320 (0.00%)
Septic shock ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Soft tissue infection ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Tuberculosis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Upper respiratory tract infection ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Urinary tract infection ^† 1	7/320 (2.19%)	0/50 (0.00%)	5/320 (1.56%)
Injury, poisoning and procedural complications
Clavicle fracture ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Compression fracture ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Fall ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Femur fracture ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Infusion related reaction ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Lumbar vertebral fracture ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Overdose ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Radiation injury ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Spinal compression fracture ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Spinal fracture ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Toxicity to various agents ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Investigations
Alanine aminotransferase increased ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Aspartate aminotransferase increased ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Bordetella test positive ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Ejection fraction decreased ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Escherichia test positive ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Hepatic enzyme increased ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Human rhinovirus test positive ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Influenza A virus test positive ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Liver function test abnormal ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Platelet count decreased ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Transaminases increased ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	0/320 (0.00%)	0/50 (0.00%)	3/320 (0.94%)
Dehydration ^† 1	3/320 (0.94%)	0/50 (0.00%)	2/320 (0.63%)
Electrolyte imbalance ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Hypercalcaemia ^† 1	0/320 (0.00%)	0/50 (0.00%)	4/320 (1.25%)
Hyperglycaemia ^† 1	2/320 (0.63%)	1/50 (2.00%)	3/320 (0.94%)
Hyperkalaemia ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Hypoglycaemia ^† 1	2/320 (0.63%)	0/50 (0.00%)	1/320 (0.31%)
Hyponatraemia ^† 1	7/320 (2.19%)	1/50 (2.00%)	5/320 (1.56%)
Metabolic disorder ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Arthritis ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Back pain ^† 1	3/320 (0.94%)	0/50 (0.00%)	4/320 (1.25%)
Bone lesion ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Bone pain ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Flank pain ^† 1	0/320 (0.00%)	0/50 (0.00%)	3/320 (0.94%)
Intervertebral disc protrusion ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Limb discomfort ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Lumbar spinal stenosis ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Muscular weakness ^† 1	1/320 (0.31%)	0/50 (0.00%)	2/320 (0.63%)
Musculoskeletal chest pain ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Neck pain ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Osteoarthritis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Osteolysis ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Pain in extremity ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Pathological fracture ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Polyarthritis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Trismus ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Bladder neoplasm ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Bowen's disease ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Cancer pain ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Clear cell renal cell carcinoma ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Intracranial tumour haemorrhage ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Malignant neoplasm progression ^† 1	24/320 (7.50%)	4/50 (8.00%)	23/320 (7.19%)
Metastases to bone ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Metastases to central nervous system ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Metastases to spine ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Neoplasm progression ^† 1	2/320 (0.63%)	0/50 (0.00%)	4/320 (1.25%)
Renal cancer ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Renal cancer recurrent ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Squamous cell carcinoma ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Tumour associated fever ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Tumour pain ^† 1	3/320 (0.94%)	0/50 (0.00%)	1/320 (0.31%)
Nervous system disorders
Altered state of consciousness ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Aphasia ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Central nervous system lesion ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Cerebral haemorrhage ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Cerebral ischaemia ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Dizziness ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Encephalopathy ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Guillain-Barre syndrome ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Haemorrhage intracranial ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Headache ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Hydrocephalus ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Ischaemic stroke ^† 1	1/320 (0.31%)	1/50 (2.00%)	0/320 (0.00%)
Lethargy ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Peripheral sensorimotor neuropathy ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Presyncope ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Sciatica ^† 1	1/320 (0.31%)	0/50 (0.00%)	2/320 (0.63%)
Seizure ^† 1	2/320 (0.63%)	0/50 (0.00%)	2/320 (0.63%)
Syncope ^† 1	2/320 (0.63%)	2/50 (4.00%)	1/320 (0.31%)
Psychiatric disorders
Confusional state ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Delirium ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Renal and urinary disorders
Acute kidney injury ^† 1	2/320 (0.63%)	0/50 (0.00%)	6/320 (1.88%)
Azotaemia ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Bladder tamponade ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Haematuria ^† 1	0/320 (0.00%)	0/50 (0.00%)	3/320 (0.94%)
Nephritis ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Proteinuria ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Renal colic ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Renal failure ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Urinary retention ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Reproductive system and breast disorders
Benign prostatic hyperplasia ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Ovarian cyst ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Prostatitis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure ^† 1	0/320 (0.00%)	0/50 (0.00%)	2/320 (0.63%)
Asthma ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Chronic obstructive pulmonary disease ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Cough ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Dyspnoea ^† 1	3/320 (0.94%)	1/50 (2.00%)	3/320 (0.94%)
Haemoptysis ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Hypoxia ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Mediastinal haemorrhage ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Oropharyngeal pain ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Pleural effusion ^† 1	2/320 (0.63%)	0/50 (0.00%)	9/320 (2.81%)
Pneumonitis ^† 1	9/320 (2.81%)	0/50 (0.00%)	1/320 (0.31%)
Pulmonary artery thrombosis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Pulmonary embolism ^† 1	9/320 (2.81%)	0/50 (0.00%)	3/320 (0.94%)
Respiratory distress ^† 1	0/320 (0.00%)	0/50 (0.00%)	1/320 (0.31%)
Respiratory failure ^† 1	1/320 (0.31%)	0/50 (0.00%)	9/320 (2.81%)
Skin and subcutaneous tissue disorders
Dermatitis ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Palmar-plantar erythrodysaesthesia syndrome ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Peau d'orange ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Pemphigoid ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Rash ^† 1	1/320 (0.31%)	1/50 (2.00%)	0/320 (0.00%)
Rash erythematous ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Rash papular ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Skin exfoliation ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Skin ulcer ^† 1	2/320 (0.63%)	0/50 (0.00%)	0/320 (0.00%)
Surgical and medical procedures
Central venous catheterisation ^† 1	0/320 (0.00%)	1/50 (2.00%)	0/320 (0.00%)
Surgery ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Vascular disorders
Arterial thrombosis ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Bleeding varicose vein ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Deep vein thrombosis ^† 1	3/320 (0.94%)	0/50 (0.00%)	1/320 (0.31%)
Embolism ^† 1	2/320 (0.63%)	0/50 (0.00%)	1/320 (0.31%)
Hypertension ^† 1	3/320 (0.94%)	0/50 (0.00%)	1/320 (0.31%)
Hypotension ^† 1	1/320 (0.31%)	1/50 (2.00%)	3/320 (0.94%)
Peripheral ischaemia ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Thrombosis ^† 1	1/320 (0.31%)	0/50 (0.00%)	1/320 (0.31%)
Vascular occlusion ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
Venous thrombosis limb ^† 1	1/320 (0.31%)	0/50 (0.00%)	0/320 (0.00%)
1 Term from vocabulary, 22.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Treatment A	Treatment B	Treatment C
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	316/320 (98.75%)	48/50 (96.00%)	306/320 (95.63%)
Blood and lymphatic system disorders
Anaemia ^† 1	48/320 (15.00%)	8/50 (16.00%)	85/320 (26.56%)
Leukopenia ^† 1	7/320 (2.19%)	0/50 (0.00%)	24/320 (7.50%)
Neutropenia ^† 1	15/320 (4.69%)	4/50 (8.00%)	50/320 (15.63%)
Thrombocytopenia ^† 1	25/320 (7.81%)	3/50 (6.00%)	62/320 (19.38%)
Endocrine disorders
Hyperthyroidism ^† 1	31/320 (9.69%)	3/50 (6.00%)	9/320 (2.81%)
Hypothyroidism ^† 1	109/320 (34.06%)	15/50 (30.00%)	95/320 (29.69%)
Gastrointestinal disorders
Abdominal distension ^† 1	5/320 (1.56%)	3/50 (6.00%)	7/320 (2.19%)
Abdominal pain ^† 1	50/320 (15.63%)	9/50 (18.00%)	25/320 (7.81%)
Abdominal pain upper ^† 1	22/320 (6.88%)	6/50 (12.00%)	21/320 (6.56%)
Colitis ^† 1	6/320 (1.88%)	4/50 (8.00%)	1/320 (0.31%)
Constipation ^† 1	39/320 (12.19%)	12/50 (24.00%)	41/320 (12.81%)
Diarrhoea ^† 1	202/320 (63.13%)	28/50 (56.00%)	151/320 (47.19%)
Dry mouth ^† 1	21/320 (6.56%)	3/50 (6.00%)	12/320 (3.75%)
Dyspepsia ^† 1	26/320 (8.13%)	4/50 (8.00%)	40/320 (12.50%)
Gastritis ^† 1	9/320 (2.81%)	4/50 (8.00%)	7/320 (2.19%)
Gastrooesophageal reflux disease ^† 1	25/320 (7.81%)	4/50 (8.00%)	36/320 (11.25%)
Nausea ^† 1	86/320 (26.88%)	15/50 (30.00%)	99/320 (30.94%)
Oral dysaesthesia ^† 1	2/320 (0.63%)	3/50 (6.00%)	0/320 (0.00%)
Stomatitis ^† 1	54/320 (16.88%)	8/50 (16.00%)	82/320 (25.62%)
Vomiting ^† 1	53/320 (16.56%)	10/50 (20.00%)	66/320 (20.63%)
General disorders
Asthenia ^† 1	71/320 (22.19%)	13/50 (26.00%)	58/320 (18.13%)
Chest pain ^† 1	8/320 (2.50%)	3/50 (6.00%)	8/320 (2.50%)
Fatigue ^† 1	102/320 (31.87%)	19/50 (38.00%)	112/320 (35.00%)
Malaise ^† 1	12/320 (3.75%)	2/50 (4.00%)	17/320 (5.31%)
Mucosal inflammation ^† 1	66/320 (20.63%)	13/50 (26.00%)	80/320 (25.00%)
Oedema peripheral ^† 1	35/320 (10.94%)	8/50 (16.00%)	28/320 (8.75%)
Pain ^† 1	16/320 (5.00%)	4/50 (8.00%)	17/320 (5.31%)
Pyrexia ^† 1	38/320 (11.88%)	12/50 (24.00%)	25/320 (7.81%)
Hepatobiliary disorders
Hepatotoxicity ^† 1	16/320 (5.00%)	10/50 (20.00%)	12/320 (3.75%)
Immune system disorders
Hypersensitivity ^† 1	4/320 (1.25%)	3/50 (6.00%)	4/320 (1.25%)
Infections and infestations
Bronchitis ^† 1	9/320 (2.81%)	3/50 (6.00%)	7/320 (2.19%)
Nasopharyngitis ^† 1	22/320 (6.88%)	5/50 (10.00%)	14/320 (4.38%)
Upper respiratory tract infection ^† 1	35/320 (10.94%)	5/50 (10.00%)	12/320 (3.75%)
Urinary tract infection ^† 1	23/320 (7.19%)	9/50 (18.00%)	17/320 (5.31%)
Injury, poisoning and procedural complications
Infusion related reaction ^† 1	3/320 (0.94%)	3/50 (6.00%)	1/320 (0.31%)
Investigations
Alanine aminotransferase increased ^† 1	90/320 (28.13%)	21/50 (42.00%)	28/320 (8.75%)
Amylase increased ^† 1	48/320 (15.00%)	8/50 (16.00%)	29/320 (9.06%)
Aspartate aminotransferase increased ^† 1	82/320 (25.62%)	16/50 (32.00%)	36/320 (11.25%)
Blood alkaline phosphatase increased ^† 1	37/320 (11.56%)	8/50 (16.00%)	27/320 (8.44%)
Blood bilirubin increased ^† 1	18/320 (5.63%)	6/50 (12.00%)	13/320 (4.06%)
Blood cholesterol increased ^† 1	7/320 (2.19%)	4/50 (8.00%)	10/320 (3.13%)
Blood creatinine increased ^† 1	43/320 (13.44%)	7/50 (14.00%)	43/320 (13.44%)
Blood sodium decreased ^† 1	6/320 (1.88%)	3/50 (6.00%)	2/320 (0.63%)
Blood thyroid stimulating hormone decreased ^† 1	1/320 (0.31%)	5/50 (10.00%)	2/320 (0.63%)
Blood thyroid stimulating hormone increased ^† 1	27/320 (8.44%)	3/50 (6.00%)	20/320 (6.25%)
Lipase increased ^† 1	54/320 (16.88%)	13/50 (26.00%)	38/320 (11.88%)
Lymphocyte count decreased ^† 1	6/320 (1.88%)	3/50 (6.00%)	10/320 (3.13%)
Neutrophil count decreased ^† 1	12/320 (3.75%)	2/50 (4.00%)	27/320 (8.44%)
Platelet count decreased ^† 1	18/320 (5.63%)	6/50 (12.00%)	60/320 (18.75%)
Transaminases increased ^† 1	12/320 (3.75%)	4/50 (8.00%)	5/320 (1.56%)
Weight decreased ^† 1	36/320 (11.25%)	8/50 (16.00%)	10/320 (3.13%)
White blood cell count decreased ^† 1	7/320 (2.19%)	4/50 (8.00%)	18/320 (5.63%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	92/320 (28.75%)	15/50 (30.00%)	66/320 (20.63%)
Hyperglycaemia ^† 1	28/320 (8.75%)	3/50 (6.00%)	14/320 (4.38%)
Hyperkalaemia ^† 1	21/320 (6.56%)	4/50 (8.00%)	6/320 (1.88%)
Hypoalbuminaemia ^† 1	18/320 (5.63%)	4/50 (8.00%)	12/320 (3.75%)
Hypocalcaemia ^† 1	22/320 (6.88%)	4/50 (8.00%)	7/320 (2.19%)
Hypoglycaemia ^† 1	4/320 (1.25%)	3/50 (6.00%)	5/320 (1.56%)
Hypokalaemia ^† 1	18/320 (5.63%)	2/50 (4.00%)	11/320 (3.44%)
Hypomagnesaemia ^† 1	44/320 (13.75%)	3/50 (6.00%)	15/320 (4.69%)
Hyponatraemia ^† 1	48/320 (15.00%)	8/50 (16.00%)	28/320 (8.75%)
Hypophosphataemia ^† 1	46/320 (14.37%)	6/50 (12.00%)	18/320 (5.63%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	59/320 (18.44%)	7/50 (14.00%)	29/320 (9.06%)
Back pain ^† 1	56/320 (17.50%)	11/50 (22.00%)	38/320 (11.88%)
Muscle spasms ^† 1	38/320 (11.88%)	7/50 (14.00%)	5/320 (1.56%)
Musculoskeletal pain ^† 1	17/320 (5.31%)	3/50 (6.00%)	10/320 (3.13%)
Musculoskeletal stiffness ^† 1	1/320 (0.31%)	3/50 (6.00%)	2/320 (0.63%)
Myalgia ^† 1	16/320 (5.00%)	11/50 (22.00%)	23/320 (7.19%)
Pain in extremity ^† 1	30/320 (9.38%)	6/50 (12.00%)	29/320 (9.06%)
Nervous system disorders
Dizziness ^† 1	32/320 (10.00%)	9/50 (18.00%)	19/320 (5.94%)
Dysgeusia ^† 1	76/320 (23.75%)	9/50 (18.00%)	70/320 (21.88%)
Headache ^† 1	50/320 (15.63%)	9/50 (18.00%)	36/320 (11.25%)
Paraesthesia ^† 1	11/320 (3.44%)	3/50 (6.00%)	8/320 (2.50%)
Psychiatric disorders
Anxiety ^† 1	8/320 (2.50%)	4/50 (8.00%)	9/320 (2.81%)
Depression ^† 1	15/320 (4.69%)	3/50 (6.00%)	9/320 (2.81%)
Insomnia ^† 1	27/320 (8.44%)	6/50 (12.00%)	17/320 (5.31%)
Renal and urinary disorders
Proteinuria ^† 1	33/320 (10.31%)	2/50 (4.00%)	25/320 (7.81%)
Renal failure ^† 1	10/320 (3.13%)	3/50 (6.00%)	4/320 (1.25%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	58/320 (18.13%)	14/50 (28.00%)	51/320 (15.94%)
Dysphonia ^† 1	56/320 (17.50%)	7/50 (14.00%)	11/320 (3.44%)
Dyspnoea ^† 1	30/320 (9.38%)	6/50 (12.00%)	27/320 (8.44%)
Epistaxis ^† 1	22/320 (6.88%)	2/50 (4.00%)	32/320 (10.00%)
Oropharyngeal pain ^† 1	30/320 (9.38%)	5/50 (10.00%)	11/320 (3.44%)
Pulmonary embolism ^† 1	12/320 (3.75%)	3/50 (6.00%)	3/320 (0.94%)
Rhinorrhoea ^† 1	12/320 (3.75%)	3/50 (6.00%)	3/320 (0.94%)
Skin and subcutaneous tissue disorders
Alopecia ^† 1	17/320 (5.31%)	3/50 (6.00%)	6/320 (1.88%)
Dry skin ^† 1	21/320 (6.56%)	2/50 (4.00%)	15/320 (4.69%)
Palmar-plantar erythrodysaesthesia syndrome ^† 1	128/320 (40.00%)	20/50 (40.00%)	130/320 (40.63%)
Pruritus ^† 1	60/320 (18.75%)	11/50 (22.00%)	15/320 (4.69%)
Rash ^† 1	69/320 (21.56%)	15/50 (30.00%)	26/320 (8.13%)
Rash maculo-papular ^† 1	27/320 (8.44%)	5/50 (10.00%)	6/320 (1.88%)
Yellow skin ^† 1	0/320 (0.00%)	1/50 (2.00%)	22/320 (6.88%)
Vascular disorders
Hypertension ^† 1	112/320 (35.00%)	18/50 (36.00%)	121/320 (37.81%)
Hypotension ^† 1	13/320 (4.06%)	4/50 (8.00%)	3/320 (0.94%)
1 Term from vocabulary, 22.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Bristol-Myers Squibb Study Director
Organization:	Bristol-Myers Squibb
Phone:	Please Email:
EMail:	Clinical.Trials@bms.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Apolo AB, Powles T, Escudier B, Burotto M, Zhang J, Simsek B, Scheffold C, Motzer RJ, Choueiri TK. Nivolumab plus ipilimumab plus cabozantinib triplet combination for patients with previously untreated advanced renal cell carcinoma: Results from a discontinued arm of the phase III CheckMate 9ER trial. Eur J Cancer. 2022 Dec;177:63-71. doi: 10.1016/j.ejca.2022.09.020. Epub 2022 Oct 4.

Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suarez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. doi: 10.1016/S1470-2045(22)00290-X. Epub 2022 Jun 7. Erratum In: Lancet Oncol. 2022 Jul;23(7):e319. Lancet Oncol. 2022 Sep;23(9):e404.

Cella D, Motzer RJ, Suarez C, Blum SI, Ejzykowicz F, Hamilton M, Wallace JF, Simsek B, Zhang J, Ivanescu C, Apolo AB, Choueiri TK. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Feb;23(2):292-303. doi: 10.1016/S1470-2045(21)00693-8. Epub 2022 Jan 12.

Hamuro L, Hu Z, Passarell J, Barcomb H, Zhang J, Goldstein S, Bello A, Roy A, Zhu L. Exposure-Response Analysis to Support Nivolumab Once Every 4 Weeks Dosing in Combination with Cabozantinib in Renal Cell Carcinoma. Clin Cancer Res. 2022 Apr 14;28(8):1603-1613. doi: 10.1158/1078-0432.CCR-21-3149.

Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juarez VM, Hsieh JJ, Basso U, Shah AY, Suarez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Zolnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. doi: 10.1056/NEJMoa2026982.

Hofmann F, Hwang EC, Lam TB, Bex A, Yuan Y, Marconi LS, Ljungberg B. Targeted therapy for metastatic renal cell carcinoma. Cochrane Database Syst Rev. 2020 Oct 14;10(10):CD012796. doi: 10.1002/14651858.CD012796.pub2.

Layout table for additonal information

Responsible Party:	Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT03141177
Other Study ID Numbers:	CA209-9ER 2017-000759-20 ( EudraCT Number )
First Submitted:	May 3, 2017
First Posted:	May 4, 2017
Results First Submitted:	February 11, 2022
Results First Posted:	April 26, 2022
Last Update Posted:	January 17, 2024

To Top