PH 1 Biomarker Study of Nivolumab and Ipilimumab and Nivolumab in Combination With Ipilimumab in Advanced Melanoma (PD-1)

• ClinicalTrials.gov Identifier: NCT01621490
• Recruitment Status: Completed
• First Posted: June 18, 2012
• Results First Posted: December 3, 2019
• Last Update Posted: December 3, 2019
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science
• Conditions: Advanced Melanoma; Metastatic Melanoma
• Interventions: Biological: Nivolumab; Drug: Ipilimumab
• Enrollment: 227

Participant Flow

Recruitment Details
Pre-assignment Details	227 participants were enrolled; 55 did not enter the treatment period: 41 did not meet study criteria; 6 other; 5 withdrew consent; 1 adverse events; 2 deaths. 172 entered the treatment period.2 were not treated;1 received ipilimumab monotherapy prior to the closure of Arm C; 1 received an unplanned treatment;168 were treated

Arm/Group Title	N3 60 M Naive	N3 60M Prog	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M +I3 90M, WU	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N1 30M +I3 30M BM	N3 30M BM
Arm/Group Description	Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; 30M = 30 minute infusion; NAIVE = Anti-CTLA4 Naive	Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W4 = Week 4 Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg;30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases
Period Title: Overall Study
Started	41	44	11	10	6	25	11	10	10
Completed [1]	0	0	0	1	0	1	0	0	2
Not Completed	41	44	11	9	6	24	11	10	8
Reason Not Completed
Participant completed treatment	4	4	1	0	0	0	0	1	0
Patient could not travel	1	0	0	0	0	0	0	0	0
Subject no longer meets study criteria	0	0	0	0	1	0	0	0	0
Maximum clinical benefit	3	2	0	0	0	0	1	2	0
Withdrawal by Subject	1	0	0	0	0	3	0	0	0
Subject request to discontinue study	1	3	1	1	0	2	1	0	1
Adverse event unrelated to study drug	2	1	0	0	0	0	0	2	1
Disease progression	27	28	1	5	3	8	7	0	4
Study drug toxicity	1	4	5	3	1	10	1	4	1
Death	0	0	0	0	0	0	0	1	0
Grade 4 Lipase elevation	1	0	0	0	0	0	0	0	0
BMS informed of patient status	0	0	1	0	0	0	0	0	0
Investigator decision	0	0	1	0	1	0	1	0	0
Documented disease progression	0	0	1	0	0	0	0	0	0
Patient reached treatment 2 yr limit	0	1	0	0	0	0	0	0	0
Clinical deterioration	0	1	0	0	0	0	0	0	0
Complete response	0	0	0	0	0	0	0	0	1
Patient delayed due to toxicity	0	0	0	0	0	1	0	0	0
[1] Completed = completed treatment period

Baseline Characteristics

Arm/Group Title		N3 60 M Naive	N3 60M Prog	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M +I3 90M, WU	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N1 30M +I3 30M BM	N3 30M BM	Total
Arm/Group Description		Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; 30M = 30 minute infusion; NAIVE = Anti-CTLA4 Naive	Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W4 = Week 4 Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg;30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Total of all reporting groups
Overall Number of Baseline Participants		41	44	11	10	6	25	11	10	10	168
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	41 participants	44 participants	11 participants	10 participants	6 participants	25 participants	11 participants	10 participants	10 participants	168 participants
		55.5 (12.49)	53.7 (15.10)	61.0 (11.82)	58.5 (13.29)	56.8 (9.64)	56.9 (13.52)	51.5 (15.55)	56.9 (9.37)	58.9 (13.46)	55.8 (13.33)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	41 participants	44 participants	11 participants	10 participants	6 participants	25 participants	11 participants	10 participants	10 participants	168 participants
	Female	19 46.3%	18 40.9%	3 27.3%	4 40.0%	3 50.0%	8 32.0%	4 36.4%	4 40.0%	5 50.0%	68 40.5%
	Male	22 53.7%	26 59.1%	8 72.7%	6 60.0%	3 50.0%	17 68.0%	7 63.6%	6 60.0%	5 50.0%	100 59.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	41 participants	44 participants	11 participants	10 participants	6 participants	25 participants	11 participants	10 participants	10 participants	168 participants
	Hispanic or Latino	2 4.9%	0 0.0%	2 18.2%	0 0.0%	0 0.0%	0 0.0%	1 9.1%	1 10.0%	0 0.0%	6 3.6%
	Not Hispanic or Latino	34 82.9%	41 93.2%	6 54.5%	10 100.0%	5 83.3%	15 60.0%	5 45.5%	3 30.0%	7 70.0%	126 75.0%
	Unknown or Not Reported	5 12.2%	3 6.8%	3 27.3%	0 0.0%	1 16.7%	10 40.0%	5 45.5%	6 60.0%	3 30.0%	36 21.4%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	41 participants	44 participants	11 participants	10 participants	6 participants	25 participants	11 participants	10 participants	10 participants	168 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	1 2.3%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 0.6%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	White	41 100.0%	43 97.7%	11 100.0%	10 100.0%	6 100.0%	25 100.0%	11 100.0%	10 100.0%	10 100.0%	167 99.4%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors
Description	Baseline and post-treatment modulation of serum levels of chemokines, cytokines and other immune mediators were assessed by techniques that included ELISA or other multiplex-based assay methods. Primary analysis included IFN-gamma and IFN-gamma inducible factors, including chemokine [C-X-C motif] ligand 9 (CXCL9) and CXCL10
Time Frame	From last non-missing value prior to first dose to week 7 day 1

Outcome Measure Data

Analysis Population Description

All response evaluable participants

Arm/Group Title		N3 60M Naive	N3 60M PROG	N1 60M + I3 90M	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N1 30M + I3 30M BM	N3 30M BM	N1+ I3 Non-BM	Naive Nivo Mono	All Nivo	All Combo	Total
Arm/Group Description:		Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive	Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Progressed	Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute	Treatment Group: Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases	Treatment Group: Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases	Treatment Group: Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases	Treatment Group: Part 4: Nivolumab 3 mg/kg 30 Minute Infusion Brain Metastases	Treatment Group: Part 2+3: Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Non-Brain Metastases	Nivolumab Monotherapy CTLA-4 Naive	Treatment Group: All Nivolumab Monotherapy	Treatment Group: All Combination Therapy	All treatments
Overall Number of Participants Analyzed		40	40	27	23	11	8	7	50	58	98	58	156
Median (Standard Deviation); Unit of Measure: pg/mL
IFN-gamma Simoa	Number Analyzed	33 participants	33 participants	19 participants	12 participants	5 participants	6 participants	6 participants	31 participants	44 participants	77 participants	37 participants	114 participants
		0.0130 (0.1740)	0.0320 (0.0817)	0.2310 (0.4528)	0.1600 (1.2047)	0.0520 (0.1207)	0.0950 (1.5082)	0.0375 (0.1868)	0.2200 (0.8198)	0.0130 (0.1674)	0.0240 (0.1373)	0.1520 (1.0023)	0.0515 (0.5944)
CXL9 (aka MIG)	Number Analyzed	33 participants	33 participants	19 participants	12 participants	5 participants	6 participants	6 participants	31 participants	44 participants	77 participants	37 participants	114 participants
		1105.0 (10467.4)	1890.0 (8706.0)	4680.0 (18096.9)	3542.0 (12133.1)	-29.0 (1684.2)	5692.0 (6796.0)	3610.0 (2197.4)	458.5 (1651.0)	1056.5 (9167.8)	1235.0 (8984.2)	4680.0 (14792.5)	2027.0 (11491.9)
CXL10 (aka IP10)	Number Analyzed	33 participants	33 participants	19 participants	12 participants	5 participants	6 participants	6 participants	31 participants	44 participants	77 participants	37 participants	114 participants
		184.0 (514.1)	160.0 (539.9)	684.0 (2563.1)	934.5 (2842.0)	26.0 (172.7)	514.0 (612.3)	318.0 (354.0)	695.0 (2627.7)	185.0 (474.6)	184.0 (500.7)	684.0 (2450.6)	234.5 (1566.3)

2. Primary Outcome

Title	Tumor Infiltrating Lymphocytes (TILs) as Measured by Medians in Percent Positive CD8 and Positive CD4 at Baseline and On-treatment Biopsy, Both Using the Mosaic Singleplex IHC Assay
Description	Biomarkers examined were percent positive CD8 and percent positive CD4, both using the Mosaic Singleplex IHC assay. Analyses are presented with the medians at baseline and on-treatment, rather than the median change because the baseline values differed across groups. Baseline was defined as the last non-missing value on or prior to the first dose of study therapy. Biopsies were also collected on treatment.
Time Frame	From last non-missing value prior to first dose to week 4 day 1

Outcome Measure Data

Analysis Population Description

Response evaluable participants

Arm/Group Title		N3 60M Naive	N3 60M PROG	N1 60M + I3 90M W2	N1 60M + I3 90M W4	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N3 30M + I3 30M BM	N3 30M BM	Nivo Mono	Nivo Mono Reduced Infusion	Week 2 Biopsy Combo	Week 2 Biopsy Non-BM Combo	Naive Nivo Mono Non-BM	N1 + I3 Non-BM
Arm/Group Description:		Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive	Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Progressed	Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion Week 2 Biopsy	Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion Week 4 Biopsy	Treatment Group: Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases	Treatment Group: Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases	Treatment Group: Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases	Treatment Group: Part 4: Nivolumab 3 mg/kg 30 Minute Infusion Brain Metastases	Treatment Group: Part 1: Regular Infusion Nivolumab Mono	Treatment Group: Reduced Infusion Nivolumab Monotherapy	Treatment Group: Week 2 Biopsy Combo	Treatment Group: Week 2 Biopsy Non-Brain Metastases Combo	Treatment Group: Naive Nivolumab Mono Non-Brain Metastases	Treatment Group: Part 2+3: Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Non-Brain Metastases
Overall Number of Participants Analyzed		25	23	11	10	15	10	3	2	48	12	29	26	35	40
Median (Standard Deviation); Unit of Measure: Percentage of positive cells
Percent CD8 Baseline	Number Analyzed	21 participants	21 participants	11 participants	10 participants	15 participants	10 participants	3 participants	2 participants	42 participants	12 participants	29 participants	26 participants	31 participants	40 participants
		3.73 (10.994)	7.230 (10.712)	3.260 (9.259)	11.105 (9.524)	4.700 (9.810)	5.615 (12.475)	18.590 (8.132)	6.135 (5.664)	6.360 (10.727)	5.615 (11.472)	4.700 (9.292)	4.230 (9.401)	5.210 (11.288)	4.230 (9.844)
Percent positive CD8 Week 2	Number Analyzed	0 participants	0 participants	10 participants	0 participants	8 participants	9 participants	3 participants	2 participants	0 participants	11 participants	21 participants	18 participants	9 participants	18 participants
				11.345 (21.316)		7.970 (15.132)	10.100 (10.909)	8.470 (7.740)	29.735 (5.254)		10.910 (12.387)	9.080 (17.510)	9.125 (18.654)	10.100 (10.909)	9.125 (18.654)
Percent positive CD8 Week 4	Number Analyzed	14 participants	16 participants	0 participants	6 participants	2 participants	0 participants	0 participants	0 participants	30 participants	0 participants	2 participants	2 participants	14 participants	8 participants
		18.435 (17.108)	7.140 (25.204)		32.455 (15.967)	37.465 (5.706)				15.150 (21.475)		37.465 (5.706)	37.465 (5.706)	18.435 (17.108)	34.785 (13.856)
Percent CD4 Baseline	Number Analyzed	21 participants	21 participants	11 participants	10 participants	14 participants	10 participants	3 participants	1 participants	42 participants	11 participants	28 participants	25 participants	31 participants	39 participants
		0.360 (1.844)	0.600 (2.268)	0.840 (1.852)	0.470 (3.833)	4.155 (6.624)	4.950 (4.992)	6.500 (8.108)	2.780 [1] (NA)	0.375 (2.057)	4.600 (4.807)	2.750 (5.833)	2.610 (5.607)	0.870 (3.727)	1.510 (6.023)
Percent positive CD4 Week 2	Number Analyzed	0 participants	0 participants	10 participants	0 participants	7 participants	9 participants	3 participants	1 participants	0 participants	10 participants	20 participants	17 participants	9 participants	17 participants
				4.500 (10.741)		6.260 (8.518)	4.210 (5.029)	6.420 (14.778)	20.830 [1] (NA)		6.155 (6.585)	6.125 (10.222)	5.990 (9.602)	4.210 (5.029)	5.990 (9.602)
Percent positive CD4 Week 4	Number Analyzed	14 participants	16 participants	0 participants	6 participants	2 participants	0 participants	0 participants	0 participants	30 participants	0 participants	2 participants	2 participants	14 participants	8 participants
		1.585 (3.071)	1.260 (4.641)		9.005 (13.324)	24.520 (2.659)				1.275 (3.921)		24.520 (2.659)	24.520 (2.659)	1.585 (3.071)	10.155 (12.707)

[1]

Upper limit not reached

3. Secondary Outcome

Title	Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Deaths and AEs
Description	The assessment of safety was based on frequency of deaths, AEs, SAEs, AEs leading to discontinuation of study drug, and abnormalities in specific clinical laboratory assessments. AEs were coded using the MedDRA Version 20.1 AEs and laboratory values were graded for severity according to the NCI CTCAE version 4.0.
Time Frame	Includes events reported between first dose and up to 100 days after last dose of study medication.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N3 60M Naive	N3 60M PROG	N1 60M + I3 90M	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N1 30M + I3 30M BM	N3 30M BM	N3 60M	N3 30M	N1 30M + I3 30M	N3 NAIVE	All N3	Total
Arm/Group Description:	N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion	N3 = Nivolumab 3mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg	All treatments
Overall Number of Participants Analyzed	41	44	27	25	11	10	10	85	21	35	62	106	168
Measure Type: Number; Unit of Measure: Events
Participants who died	26	25	10	12	4	2	4	51	8	14	34	59	83
Participants who died within 30 days of last dose	3	2	4	0	0	1	0	5	0	1	3	5	10
Participants who died within 100 days of last dose	5	8	5	0	1	2	2	13	3	2	8	16	23
Participants with an AE	41	44	27	25	11	10	10	85	21	35	62	106	168

4. Secondary Outcome

Title	Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by SAEs and AEs Leading to Discontinuation of Study Drug.
Description	The assessment of safety was based on frequency of SAEs and AEs leading to discontinuation of study drug. AEs were coded using the MedDRA Version 20.1 AEs and laboratory values were graded for severity according to the NCI CTCAE version 4.0.
Time Frame	From enrollment to 100 days after the last dose date

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N3 60M Naive	N3 60M Prog	N1 60M + I3 90M	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N1 30M I3 30M BM	N3 30M BM	Nivo Mono	Reduced Nivo Mono	Reduced Combo	Naive Nivo Mono	All Nivo Mono	All Combo	Total
Arm/Group Description:	Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive	Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Progressed	Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion	Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases	Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases	Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases	Part 4: Nivolumab 3 mg/kg 30 Minute Infusion Brain Metastases	Part 1: Regular Infusion Nivolumab Mono	Reduced Infusion Nivolumab Mono	Reduced Infusion Combo	Naive Nivolumab Mono	All Nivolumab Mono	All Combinations	All treatments
Overall Number of Participants Analyzed	41	44	27	25	11	10	10	85	21	35	62	106	62	168
Measure Type: Number; Unit of Measure: Events
SAEs by Worst CTC Grade	16	16	20	13	2	6	4	32	6	19	22	38	39	77
AEs Leading to Discontinuation by Worst CTC Grade	3	6	12	9	1	4	3	9	4	13	7	13	25	38

5. Secondary Outcome

Title	Number of Laboratory Abnormalities in Specific Liver Tests
Description	Abnormalities in hepatic parameters measured included those in aspartate aminotransferase (AST), alanine aminotransferase (ALT)and total bilirubin, with respect to upper limit of normal (ULN)
Time Frame	101-120 days after last dose.

Outcome Measure Data

Analysis Population Description

Participants with at least one on-treatment measurement of the corresponding laboratory parameter

Arm/Group Title		N3 60M NAIVE	N3 60M PROG	N1 60M +I3 90M	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N1 30M + I3 30M BM	N3 30M BM	N3 60M	N3 30M	N1 30M + I3 30M	N3 NAIVE	All N3	Total
Arm/Group Description:		Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg;30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg	All treatments
Overall Number of Participants Analyzed		41	44	27	25	11	10	10	85	21	35	62	106	168
Measure Type: Number; Unit of Measure: Events
ALT OR AST > 3XULN	Number Analyzed	39 participants	44 participants	24 participants	25 participants	11 participants	10 participants	8 participants	83 participants	19 participants	35 participants	58 participants	102 participants	161 participants
		2	4	8	5	0	3	0	6	0	8	2	6	22
ALT OR AST> 5XULN	Number Analyzed	39 participants	44 participants	24 participants	25 participants	11 participants	10 participants	8 participants	83 participants	19 participants	35 participants	58 participants	102 participants	161 participants
		1	2	6	4	0	1	0	3	0	5	1	3	14
ALT OR AST> 10XULN	Number Analyzed	39 participants	44 participants	24 participants	25 participants	11 participants	10 participants	8 participants	83 participants	19 participants	35 participants	62 participants	102 participants	161 participants
		1	0	3	2	0	1	0	1	0	3	1	1	7
ALT OR AST > 20XULN	Number Analyzed	39 participants	44 participants	24 participants	25 participants	11 participants	10 participants	8 participants	83 participants	19 participants	35 participants	62 participants	102 participants	161 participants
		0	0	1	0	0	1	0	0	0	1	0	0	2
TOTAL BILIRUBIN > 2XULN	Number Analyzed	39 participants	44 participants	25 participants	24 participants	11 participants	10 participants	8 participants	83 participants	19 participants	34 participants	58 participants	102 participants	161 participants
		0	0	2	1	0	2	0	0	0	3	0	0	5
ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY	Number Analyzed	39 participants	44 participants	24 participants	24 participants	11 participants	10 participants	8 participants	83 participants	19 participants	34 participants	58 participants	102 participants	160 participants
		0	0	2	1	0	1	0	0	0	2	0	0	4
ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAY	Number Analyzed	39 participants	44 participants	24 participants	24 participants	11 participants	10 participants	8 participants	83 participants	19 participants	34 participants	58 participants	102 participants	160 participants
		0	0	2	1	0	1	0	0	0	2	0	0	4

6. Secondary Outcome

Title	Number of Laboratory Abnormalities in Specific Thyroid Tests
Description	Abnormalities in thyroid parameters measured included those in thyroid stimulating hormone (TSH) levels with respect to upper limit of normal (ULN) and lower limit of normal (LLN)
Time Frame	101-120 days after last dose.

Outcome Measure Data

Analysis Population Description

Participants with at least one on-treatment measurement of TSH

Arm/Group Title	N3 60M NAIVE	N3 60M PROG	N1 60M +I3 90M	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N1 30M + I3 30M BM	N3 30M BM	N3 60M	N3 30M	N1 30M + I3 30M	N3 NAIVE	All N3	Total
Arm/Group Description:	Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg;30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg	All treatments
Overall Number of Participants Analyzed	29	33	21	25	11	10	8	62	19	35	48	81	137
Measure Type: Number; Unit of Measure: Events
TSH > ULN	9	16	7	7	1	3	4	25	5	10	14	30	47
TSH > ULN WITH TSH <= ULN AT BASELINE	4	9	7	4	1	3	2	13	3	7	7	16	30
TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN	0	0	3	3	0	2	2	0	2	5	2	2	10
TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN	0	0	0	0	0	0	0	0	0	0	0	0	0
TSH > ULN WITH FT3/FT4 TEST MISSING	9	16	4	4	1	1	2	25	3	5	12	28	37
TSH < LLN	3	4	11	12	2	6	5	7	7	18	10	14	43
TSH <LLN WITH TSH >= LLN AT BASELINE	3	4	11	12	2	6	5	7	7	18	10	14	43
TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN	0	0	5	4	0	2	2	0	2	6	2	2	13
TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN	0	0	3	1	0	0	1	0	1	1	1	1	5
TSH < LLN WITH FT3/FT4 TEST MISSING	3	4	3	7	2	4	2	7	4	11	7	11	25

7. Secondary Outcome

Title	Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Objective Response Rate (ORR)
Description	The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (eg, all treated subjects or response-evaluable subjects). The BOR was defined as the subject's best response designation, over the study as a whole, recorded between the date of first study drug administration and the date of objectively documented progression per RECIST 1.1, with subsequent confirmation, or date of subsequent anti-cancer therapy, whichever occurred first in the study.
Time Frame	Approximately every 8 weeks until disease progression and in follow-up if no progression

Outcome Measure Data

Analysis Population Description

All treated subjects

Arm/Group Title	N3 60M Naive	N3 60M Prog	N1 60M+I3 90M	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N3 30M + I3 30M BM	N3 30M BM	N1 + I3 Non-BM	N3 Naive	N3 Only	N1 + I3	Total
Arm/Group Description:	N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed;	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases;	N3 = Nivolumab 3mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg	All combination treatments	All treatments
Overall Number of Participants Analyzed	41	44	27	25	11	10	10	52	62	106	62	168
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	31.7; (18.1 to 48.1)	22.7; (11.5 to 37.8)	44.4; (25.5 to 64.7)	40.0; (21.1 to 61.3)	27.3; (6.0 to 61.0)	70.0; (34.8 to 93.3)	60.0; (26.2 to 87.8)	42.3; (28.7 to 56.8)	35.5; (23.7 to 48.7)	30.2; (21.7 to 39.9)	46.8; (34.0 to 59.9)	36.3; (29.0 to 44.1)

8. Secondary Outcome

Title	Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Duration of Response (mDOR)
Description	Median duration of response (mDOR) was calculated for subjects with BOR of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication.
Time Frame	2 years from the first dose of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N3 60M Naive	N3 60M PROG	N1 60M + I3 90M	N1 30M + I3 30M NON-BM	N3 30M NON-BM	N1 30M + I3 30M BM	N3 30M BM	N1 + I3 NON-BM	N3 NAIVE	All N3	N1 + I3	Total
Arm/Group Description:	N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed;	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg	All combination treatments	All treatments
Overall Number of Participants Analyzed	41	44	27	25	11	10	10	52	62	106	62	168
Median (95% Confidence Interval); Unit of Measure: Months
	15.21 [1]; (5.55 to NA)	NA [2]; (5.55 to NA)	NA [2]; (5.85 to NA)	26.25 [1]; (7.85 to NA)	NA [2]; (3.71 to NA)	NA [2]; (22.01 to NA)	20.27 [1]; (13.57 to NA)	NA [2]; (26.25 to NA)	20.27 [1]; (11.5 to NA)	NA [2]; (13.57 to NA)	NA [2]; (26.25 to NA)	NA [2]; (22.01 to NA)

[1]

Upper limit not reached

[2]

Median not reached; Upper limit not reached

9. Secondary Outcome

Title	Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Time to Response (mTTR)
Description	Median time to response (mTTR) for a participant with a BOR of CR or PR is defined as the time from the first dosing date to the date of the first documented objective response (CR or PR).
Time Frame	2 years from the first dose of treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	N3 60M Naive	N3 60M PROG	N1 60M + I3 90M	N1 30M + I3 30M NON-BM	N3 30M NON-BM	N1 30M + I3 30M BM	N3 30M BM	N1 + I3 NON-BM	N3 NAIVE	All N3	N1 + I3	Total
Arm/Group Description:	N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed;	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg	All combination	All treatments
Overall Number of Participants Analyzed	41	44	27	25	11	10	10	52	62	106	62	168
Median (95% Confidence Interval); Unit of Measure: Months
	1.87; (1.77 to 5.29)	2.78; (1.84 to 14.59)	1.41; (1.28 to 1.87)	2.51; (1.28 to 2.86)	1.41; (1.41 to 6.90)	1.71; (1.38 to 7.43)	2.14; (1.25 to 4.99)	1.41; (1.41 to 2.56)	1.87; (1.74 to 3.71)	1.87; (1.84 to 3.68)	1.45; (1.41 to 2.50)	1.87; (1.71 to 2.50)

10. Secondary Outcome

Title	Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Progression Free Survival Rate (PFSR)
Description	The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication.
Time Frame	2 years from the first dose of treatment

Outcome Measure Data

Analysis Population Description

All treated subjects

Arm/Group Title	N3 60M Naive	N3 60M PROG	N1 60M + I3 90M	N1 30M + I3 30M NON-BM	N3 30M NON-BM	N1 30M + I3 30M BM	N3 30M BM	N1 + I3 NON-BM	N3 NAIVE	All N3	N1 + I3	Total
Arm/Group Description:	N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed;	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg	All combination treatments	All treatments
Overall Number of Participants Analyzed	41	44	27	25	11	10	10	52	62	106	62	168
Median (95% Confidence Interval); Unit of Measure: Percentage
	3.68; (1.84 to 7.36)	5.62; (1.87 to 9.66)	7.00 [1]; (1.41 to NA)	9.69; (1.94 to 29.01)	4.93 [1]; (1.41 to NA)	NA [2]; (1.18 to NA)	23.00 [1]; (0.85 to NA)	7.23 [1]; (1.94 to NA)	3.91; (1.94 to 10.58)	4.93; (2.17 to 8.77)	10.55 [1]; (2.79 to NA)	5.78; (3.29 to 9.66)

[1]

Upper limit not reached

[2]

Median and upper limit not reached

11. Secondary Outcome

Title	Immunogenicity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Serum Anti-drug Antibody (ADA) Positive Participants and the Number of Neutralizing ADA Positive Participants
Description	Time Frame: Part 1: Day 1, Day 15, Day 43 of cycle 1, Day 1 of cycle 2, Day 15 of cycle 3, every 16 weeks after cycle 3 up to 2 years, follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment) Part 2, 3 and 4: Weeks 1, 3, 4, 7, 9, 10, 13, 25, 53, 79, 95 follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment)
Time Frame	Up to follow-up visit 2 (101-120 days since last treatment)

Outcome Measure Data

Analysis Population Description

A subset of all treated subjects who had a baseline and at least 1 post-baseline ADA assessment for nivolumab and ipilimumab separately

Arm/Group Title		N3 60M NAIVE	N3 60M PROG	N1 60M + I3 (Nivo ADA	N1 60M + I3 90M (Ipi ADA)	N1 30M + I3 30M Non-BM (Nivo ADA)	N1 30M + I3 30M Non-BM (Ipi ADA)	N3 30M Non-BM	N1 30M + I3 30M (Nivo ADA)	N1 30M + I3 30M (Ipi ADA)	N3 30M BM	Total (Nivo ADA)	Total (Ipi ADA)
Arm/Group Description:		Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive	Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Progressed	Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute	Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute	Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases	Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases	Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases	Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases	Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases	Part 4: Nivolumab 3 mg/kg 30 Minute Infusion Brain Metastases	Total (All Nivolumab or Nivolumab + Ipilimumab Treated Subjects with Baseline and at Least One Post-Baseline Assessment)	Total (All Nivolumab or Nivolumab + Ipilimumab Treated Subjects with Baseline and at Least One Post-Baseline Assessment)
Overall Number of Participants Analyzed		38	42	22	22	24	23	11	10	9	7	154	54
Measure Type: Number; Unit of Measure: Participants
ADA positive	Number Analyzed	38 participants	42 participants	22 participants	22 participants	24 participants	23 participants	11 participants	10 participants	9 participants	7 participants	154 participants	54 participants
		2	5	10	1	16	4	1	7	0	1	42	5
Neutralizing ADA positive	Number Analyzed	2 participants	5 participants	10 participants	1 participants	16 participants	4 participants	1 participants	7 participants	0 participants	1 participants	42 participants	5 participants
		0	0	0	0	1	0	0	2		0	3	0

12. Secondary Outcome

Title	Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Objective Response Rate (PD-L1 ORR)
Description	For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (all response-evaluable participants).
Time Frame	2 years from first dose of treatment; Assessed up to September 2017

Outcome Measure Data

Analysis Population Description

All response-evaluable participants

Arm/Group Title		N3 60M NAIVE, W4	N3 60M PROG, W4	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M + I3 90M, WU	N1 30M + I3 30M NON-BM	N3 30M NON-BM, W2	N1 30M + I3 30M BM, W2	N3 30M BM, W2	N3 60M, W4	N3 30M, W2	N1 + I3, W2	N1 + I3 W2, NON-BM	N3 NAIVE, NON-BM	N1 + I3 NON-BM	Total
Arm/Group Description:		Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; 30M = 30 minute infusion; W4 = Week 4 Biopsy;	Treatment Group: N3 = Nivolumab 3mg/kg; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	All treatments
Overall Number of Participants Analyzed		39	36	11	10	6	22	9	4	3	75	12	37	33	48	49	140
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage
STTU 1 - 1% Level PD-L1 Status: Met criteria	Number Analyzed	20 participants	17 participants	7 participants	6 participants	2 participants	11 participants	5 participants	2 participants	1 participants	37 participants	6 participants	20 participants	18 participants	25 participants	26 participants	71 participants
		40.0; (19.1 to 63.9)	35.3; (14.2 to 61.7)	85.7; (42.1 to 99.6)	50.0; (11.8 to 88.2)	50.0; (1.3 to 98.7)	63.6; (30.8 to 89.1)	40.0; (5.3 to 85.3)	100.0; (15.8 to 100.0)	100.0; (2.5 to 100.0)	37.8; (22.5 to 55.2)	50.0; (11.8 to 88.2)	75.0; (50.9 to 91.3)	72.2; (46.5 to 90.3)	40.0; (21.1 to 61.3)	65.4; (44.3 to 82.8)	50.7; (38.6 to 62.8)
STTU 1 - 5% Level PD-L1 Status: Met criteria	Number Analyzed	10 participants	9 participants	5 participants	5 participants	1 participants	7 participants	2 participants	2 participants	1 participants	19 participants	3 participants	14 participants	12 participants	12 participants	18 participants	42 participants
		40.0; (12.2 to 73.8)	33.3; (7.5 to 70.1)	80.0; (28.4 to 99.5)	60.0; (14.7 to 94.7)	100.0; (2.5 to 100.0)	71.4; (29.0 to 96.3)	50.0; (1.3 to 98.7)	100.0; (15.8 to 100.0)	100.0; (2.5 to 100.0)	36.8; (16.3 to 61.6)	66.7; (9.4 to 99.2)	78.6; (49.2 to 95.3)	75.0; (42.8 to 94.5)	41.7; (15.2 to 72.3)	72.2; (46.5 to 90.3)	57.1; (41.0 to 72.3)
STTU 1 - 10% Level PD-L1 Status: Met criteria	Number Analyzed	7 participants	5 participants	3 participants	4 participants	1 participants	3 participants	1 participants	2 participants	1 participants	12 participants	2 participants	8 participants	6 participants	8 participants	11 participants	27 participants
		42.9; (9.9 to 81.6)	20.0; (0.5 to 71.6)	100.0; (29.2 to 100.0)	75.0; (19.4 to 99.4)	100.0; (2.5 to 100.0)	66.7; (9.4 to 99.2)	100.0; (2.5 to 100.0)	100.0; (15.8 to 100.0)	100.0; (2.5 to 100.0)	33.3; (9.9 to 65.1)	100.0; (15.8 to 100.0)	87.5; (47.3 to 99.7)	83.3; (35.9 to 99.6)	50.0; (15.7 to 84.3)	81.8; (48.2 to 97.7)	63.0; (42.4 to 80.6)

13. Secondary Outcome

Title	Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as the Duration of Response (PD-L1 DOR)
Description	For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. Median duration of response (mDOR) was calculated for all response-evaluable participants with best overall response of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication.
Time Frame	2 years from first dose of treatment; Assessed up to September 2017

Outcome Measure Data

Analysis Population Description

All response-evaluable participants

Arm/Group Title		N3 60M NAIVE, W4	N3 60M PROG, W4	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M + I3 90M, WU	N1 30M + I3 30M NON-BM	N3 30M NON-BM, W2	N1 30M + I3 30M BM, W2	N3 30M BM, W2	N3 60M, W4	N3 30M, W2	N1 + I3, W2	N1 + I3 W2, NON-BM	N3 NAIVE, NON-BM	N1 + I3 NON-BM	Total
Arm/Group Description:		Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; 30M = 30 minute infusion; W4 = Week 4 Biopsy;	Treatment Group: N3 = Nivolumab 3mg/kg; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	All treatments
Overall Number of Participants Analyzed		39	36	11	10	6	22	9	4	3	75	12	37	33	48	49	140
Median (95% Confidence Interval); Unit of Measure: Months
STTU 1 - 1% Level PD-L1 Status: Met criteria	Number Analyzed	20 participants	17 participants	7 participants	6 participants	2 participants	11 participants	5 participants	2 participants	1 participants	37 participants	6 participants	20 participants	18 participants	25 participants	26 participants	71 participants
		15.21; (4.60 to 18.20)	NA [1]; (15.57 to NA)	NA [1]; (2.96 to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	26.25 [3]; (8.31 to NA)	NA [1]; (3.71 to NA)	22.01 [4]; (NA to NA)	NA [2]; (NA to NA)	15.57 [3]; (11.50 to NA)	NA [1]; (3.71 to NA)	26.25 [3]; (22.01 to NA)	NA [1]; (8.31 to NA)	15.21 [3]; (3.71 to NA)	NA [1]; (26.25 to NA)	26.25 [3]; (15.57 to NA)
STTU 1 - 5% Level PD-L1 Status: Met criteria	Number Analyzed	10 participants	9 participants	5 participants	5 participants	1 participants	7 participants	2 participants	2 participants	1 participants	19 participants	3 participants	14 participants	12 participants	12 participants	18 participants	42 participants
		13.36; (4.60 to 15.21)	NA [1]; (15.57 to NA)	NA [1]; (2.96 to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	26.25 [3]; (8.31 to NA)	NA [1]; (3.71 to NA)	22.01 [4]; (NA to NA)	NA [2]; (NA to NA)	15.57 [3]; (4.60 to NA)	NA [2]; (NA to NA)	26.25 [3]; (8.31 to NA)	NA [1]; (2.96 to NA)	15.21 [3]; (4.60 to NA)	NA [1]; (8.31 to NA)	26.25 [3]; (15.21 to NA)
STTU 1 - 10% Level PD-L1 Status: Met criteria	Number Analyzed	7 participants	5 participants	3 participants	4 participants	1 participants	3 participants	1 participants	2 participants	1 participants	12 participants	2 participants	8 participants	6 participants	8 participants	11 participants	27 participants
		15.21; (4.60 to 15.21)	15.57 [4]; (NA to NA)	NA [1]; (2.96 to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [1]; (3.71 to NA)	22.01 [4]; (NA to NA)	NA [2]; (NA to NA)	15.21; (4.60 to 15.57)	NA [2]; (NA to NA)	NA [1]; (2.96 to NA)	NA [1]; (2.96 to NA)	15.21 [3]; (4.60 to NA)	NA [1]; (2.96 to NA)	NA [1]; (15.21 to NA)

[1]

Median not reached; Upper limit not reached

[2]

Median not reached; Upper and lower limits not reached

[3]

Upper limit not reached

[4]

Upper and lower limits not reached

14. Secondary Outcome

Title	Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Progression Free Survival (PD-L1 PFS)
Description	For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication.
Time Frame	2 years from first dose of treatment; Assessed up to September 2017

Outcome Measure Data

Analysis Population Description

All response-evaluable participants

Arm/Group Title		N3 60M NAIVE, W4	N3 60M PROG, W4	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M + I3 90M, WU	N1 30M + I3 30M NON-BM	N3 30M NON-BM, W2	N1 30M + I3 30M BM, W2	N3 30M BM, W2	N3 60M, W4	N3 30M, W2	N1 + I3, W2	N1 + I3 W2, NON-BM	N3 NAIVE, NON-BM	N1 + I3 NON-BM	Total
Arm/Group Description:		Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; 30M = 30 minute infusion; W4 = Week 4 Biopsy;	Treatment Group: N3 = Nivolumab 3mg/kg; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	All treatments
Overall Number of Participants Analyzed		39	36	11	10	6	22	9	4	3	75	12	37	33	48	49	140
Median (95% Confidence Interval); Unit of Measure: Months
STTU 1 - 1% Level PD-L1 Status: Met criteria	Number Analyzed	20 participants	17 participants	7 participants	6 participants	2 participants	11 participants	5 participants	2 participants	1 participants	37 participants	6 participants	20 participants	18 participants	25 participants	26 participants	71 participants
		4.50; (1.84 to 15.18)	9.66 [1]; (3.71 to NA)	NA [2]; (1.22 to NA)	NA [2]; (0.85 to NA)	NA [2]; (0.76 to NA)	29.01; (1.94 to 29.01)	8.77 [1]; (1.22 to NA)	NA [2]; (23.95 to NA)	NA [3]; (NA to NA)	6.24; (3.65 to 17.05)	8.77 [1]; (1.22 to NA)	29.01 [1]; (4.17 to NA)	29.01 [1]; (3.02 to NA)	5.36; (1.94 to 10.94)	29.01 [1]; (3.02 to NA)	10.58; (5.62 to 19.81)
STTU 1 - 5% Level PD-L1 Status: Met criteria	Number Analyzed	10 participants	9 participants	5 participants	5 participants	1 participants	7 participants	2 participants	2 participants	1 participants	19 participants	3 participants	14 participants	12 participants	12 participants	18 participants	42 participants
		6.28; (0.33 to 17.05)	19.29 [1]; (1.77 to NA)	NA [2]; (1.22 to NA)	NA [2]; (0.85 to NA)	NA [4]; (NA to NA)	29.01; (1.94 to 29.01)	NA [2]; (1.22 to NA)	NA [2]; (23.95 to NA)	NA [3]; (NA to NA)	7.20; (1.87 to 18.40)	NA [2]; (1.22 to NA)	29.01 [1]; (3.02 to NA)	29.01 [1]; (1.94 to NA)	6.28; (1.22 to 17.05)	29.01 [1]; (3.02 to NA)	17.05; (5.36 to 29.01)
STTU 1 - 10% Level PD-L1 Status: Met criteria	Number Analyzed	7 participants	5 participants	3 participants	4 participants	1 participants	3 participants	1 participants	2 participants	1 participants	12 participants	2 participants	8 participants	6 participants	8 participants	11 participants	27 participants
		5.36; (0.33 to 18.40)	19.29; (1.77 to 19.29)	NA [2]; (4.17 to NA)	NA [2]; (1.64 to NA)	NA [3]; (NA to NA)	NA [2]; (1.94 to NA)	NA [3]; (NA to NA)	NA [2]; (23.95 to NA)	NA [3]; (NA to NA)	6.24; (1.71 to 18.40)	NA [3]; (NA to NA)	NA [2]; (1.94 to NA)	NA [2]; (1.94 to NA)	11.20 [1]; (0.33 to NA)	NA [2]; (1.94 to NA)	19.29 [1]; (5.36 to NA)

[1]

Upper limit not reached

[2]

Median not reached; Upper limit not reached

[3]

Median not reached; Upper and lower limits not reached

[4]

Median not reached; Upper limit and lower limit not reached

15. Secondary Outcome

Title	Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Overall Survival Rate (PD-L1 OSR)
Description	For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The overall survival rate (OSR) for a subject was defined as the time from the date of first dose of study medication to the date of death for any cause. A subject who had not died was censored at last known date alive
Time Frame	2 years from first dose of treatment; Assessed up to September 2017

Outcome Measure Data

Analysis Population Description

Biomarker evaluable participants

Arm/Group Title		N3 60M NAIVE, W4	N3 60M PROG, W4	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M + I3 90M, WU	N1 30M + I3 30M NON-BM	N3 30M NON-BM, W2	N1 30M + I3 30M BM, W2	N3 30M BM, W2	N3 60M, W4	N3 30M, W2	N1 + I3, W2	N1 + I3 W2, NON-BM	N3 NAIVE, NON-BM	N1 + I3 NON-BM	Total
Arm/Group Description:		Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy;	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; 30M = 30 minute infusion; W4 = Week 4 Biopsy;	Treatment Group: N3 = Nivolumab 3mg/kg; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy	Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	All treatments
Overall Number of Participants Analyzed		39	36	11	10	6	22	9	4	3	75	12	37	33	48	49	140
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
STTU 1 - 1% Level; PD-L1 : Met criteria 3 months	Number Analyzed	20 participants	17 participants	7 participants	6 participants	2 participants	11 participants	5 participants	2 participants	1 participants	37 participants	6 participants	20 participants	18 participants	25 participants	26 participants	71 participants
		90.0; (65.6 to 97.4)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	83.3; (27.3 to 97.5)	NA [1]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	94.6; (80.1 to 98.6)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	92.0; (71.6 to 97.9)	92.3; (72.6 to 98.0)	94.4; (85.7 to 97.8)
STTU 1 - 1% Level PD-L1 : Met criteria 6 months	Number Analyzed	20 participants	17 participants	7 participants	6 participants	2 participants	11 participants	5 participants	2 participants	1 participants	37 participants	6 participants	20 participants	18 participants	25 participants	26 participants	71 participants
		90.0; (65.6 to 97.4)	94.1; (65.0 to 99.1)	100.0; (100.0 to 100.0)	83.3; (27.3 to 97.5)	NA [1]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	91.9; (76.9 to 97.3)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	92.0; (71.6 to 97.9)	92.3; (72.6 to 98.0)	93.0; (83.9 to 97.0)
STTU 1 - 1% Level PD-L1: Met criteria 9 months	Number Analyzed	20 participants	17 participants	7 participants	6 participants	2 participants	11 participants	5 participants	2 participants	1 participants	37 participants	6 participants	20 participants	18 participants	25 participants	26 participants	71 participants
		80.0; (55.1 to 92.0)	88.2; (60.6 to 96.9)	100.0; (100.0 to 100.0)	83.3; (27.3 to 97.5)	NA [1]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	83.8; (67.4 to 92.4)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	84.0; (62.8 to 93.7)	92.3; (72.6 to 98.0)	88.7; (78.7 to 94.2)
STTU 1 - 1% Level PD-L1 : Met criteria 12 months	Number Analyzed	20 participants	17 participants	7 participants	6 participants	2 participants	11 participants	5 participants	2 participants	1 participants	37 participants	6 participants	20 participants	18 participants	25 participants	26 participants	71 participants
		75.0; (50.0 to 88.7)	70.6; (43.1 to 86.6)	100.0; (100.0 to 100.0)	83.3; (27.3 to 97.5)	NA [1]; (NA to NA)	100.0; (100.0 to 100.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	73.0; (55.6 to 84.4)	83.3; (27.3 to 97.5)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	76.0; (54.2 to 88.4)	92.3; (72.6 to 98.0)	81.7; (70.6 to 88.9)
STTU 1 - 1% Level PD-L1: Met criteria 24 months	Number Analyzed	20 participants	17 participants	7 participants	6 participants	2 participants	11 participants	5 participants	2 participants	1 participants	37 participants	6 participants	20 participants	18 participants	25 participants	26 participants	71 participants
		55.0; (31.3 to 73.5)	44.9; (20.7 to 66.6)	100.0; (100.0 to 100.0)	83.3; (27.3 to 97.5)	NA [1]; (NA to NA)	77.9; (35.4 to 94.2)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	50.5; (33.4 to 65.3)	NA [1]; (NA to NA)	82.2; (53.9 to 94.0)	87.7; (58.8 to 96.8)	52.0; (31.2 to 69.2)	84.0; (62.8 to 93.7)	60.8; (48.2 to 71.3)
STTU 5 - 5% Level PD-L1 : Met criteria 3 months	Number Analyzed	10 participants	9 participants	5 participants	5 participants	1 participants	7 participants	2 participants	2 participants	1 participants	19 participants	3 participants	14 participants	12 participants	12 participants	18 participants	42 participants
		80.0; (40.9 to 94.6)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	100.0; (100.0 to 100.0)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	89.5; (64.1 to 97.3)	NA [2]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	83.3; (48.2 to 95.6)	94.4; (66.6 to 99.2)	92.9; (79.5 to 97.6)
STTU 5 - 5% Level PD-L1: Met criteria 6 months	Number Analyzed	10 participants	9 participants	5 participants	5 participants	1 participants	7 participants	2 participants	2 participants	1 participants	19 participants	3 participants	14 participants	12 participants	12 participants	18 participants	42 participants
		80.0; (40.9 to 94.6)	88.9; (43.3 to 98.4)	100.0; (100.0 to 100.0)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	100.0; (100.0 to 100.0)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	84.2; (58.7 to 94.6)	NA [2]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	83.3; (48.2 to 95.6)	94.4; (66.6 to 99.2)	90.5; (76.6 to 96.3)
STTU 5 - 5% Level PD-L1 : Met criteria 9 months	Number Analyzed	10 participants	9 participants	5 participants	5 participants	1 participants	7 participants	2 participants	2 participants	1 participants	19 participants	3 participants	14 participants	12 participants	12 participants	18 participants	42 participants
		80.0; (40.9 to 94.6)	88.9; (43.3 to 98.4)	100.0; (100.0 to 100.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	100.0; (100.0 to 100.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	84.2; (58.7 to 94.6)	NA [1]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	83.3; (48.2 to 95.6)	94.4; (66.6 to 99.2)	90.5; (76.6 to 96.3)
STTU 5 - 5% Level PD-L1 : Met criteria 12 months	Number Analyzed	10 participants	9 participants	5 participants	5 participants	1 participants	7 participants	2 participants	2 participants	1 participants	19 participants	3 participants	14 participants	12 participants	12 participants	18 participants	42 participants
		70.0; (32.9 to 89.2)	66.7; (28.2 to 87.8)	100.0; (100.0 to 100.0)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	100.0; (100.0 to 100.0)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	68.4; (42.8 to 84.4)	NA [2]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	75; (40.8 to 91.2)	94.4; (66.6 to 99.2)	83.3; (68.2 to 91.7)
STTU 5 - 5% Level PD-L1 : Met criteria 24 months	Number Analyzed	10 participants	9 participants	5 participants	5 participants	1 participants	7 participants	2 participants	2 participants	1 participants	19 participants	3 participants	14 participants	12 participants	12 participants	18 participants	42 participants
		50.0; (18.4 to 75.3)	NA [2]; (NA to NA)	100.0; (100.0 to 100.0)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	45.6; (22.5 to 66.1)	NA [2]; (NA to NA)	76.0; (42.2 to 91.6)	81.5; (43.5 to 95.1)	50.0; (20.8 to 73.6)	82.5; (54.9 to 94.0)	60.7; (44.0 to 73.9)
STTU 10 - 10% Level PD-L1 : Met criteria 3 months	Number Analyzed	7 participants	5 participants	3 participants	4 participants	1 participants	3 participants	1 participants	2 participants	1 participants	12 participants	2 participants	8 participants	6 participants	8 participants	11 participants	27 participants
		71.4; (25.8 to 92.0)	100.0; (100.0 to 100.0)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	83.3; (48.2 to 95.6)	NA [2]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	75.0; (31.5 to 93.1)	100.0; (100.0 to 100.0)	92.6; (73.5 to 98.1)
STTU 10 - 10% Level PD-L1 : Met criteria 6 months	Number Analyzed	7 participants	5 participants	3 participants	4 participants	1 participants	3 participants	1 participants	2 participants	1 participants	12 participants	2 participants	8 participants	6 participants	8 participants	11 participants	27 participants
		71.4; (25.8 to 92.0)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	NA [2]; (NA to NA)	75.0; (40.8 to 91.2)	NA [2]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	75.0; (31.5 to 93.1)	100.0; (100.0 to 100.0)	88.9; (69.4 to 96.3)
STTU 10 - 10% Level PD-L1: Met criteria 9 months	Number Analyzed	7 participants	5 participants	3 participants	4 participants	1 participants	3 participants	1 participants	2 participants	1 participants	12 participants	2 participants	8 participants	6 participants	8 participants	11 participants	27 participants
		71.4; (25.8 to 92.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	75.0; (40.8 to 91.2)	NA [1]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	75.0; (31.5 to 93.1)	100.0; (100.0 to 100.0)	88.9; (69.4 to 96.3)
STTU 10 - 10% Level PD-L1 : Met criteria 12 months	Number Analyzed	7 participants	5 participants	3 participants	4 participants	1 participants	3 participants	1 participants	2 participants	1 participants	12 participants	2 participants	8 participants	6 participants	8 participants	11 participants	27 participants
		71.4; (25.8 to 92.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	58.3; (27.0 to 80.1)	NA [1]; (NA to NA)	100.0; (100.0 to 100.0)	100.0; (100.0 to 100.0)	75.0; (31.5 to 93.1)	100.0; (100.0 to 100.0)	81.5; (61.1 to 91.8)
STTU 10 - 10% Level PD-L1 : Met criteria 24 months	Number Analyzed	7 participants	5 participants	3 participants	4 participants	1 participants	3 participants	1 participants	2 participants	1 participants	12 participants	2 participants	8 participants	6 participants	8 participants	11 participants	27 participants
		NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	75.0; (31.5 to 93.1)	83.3; (27.3 to 97.5)	NA [1]; (NA to NA)	90.9; (50.8 to 98.7)	62.2; (41.1 to 77.6)

[1]

Not Calculated, fewer than 5 subjects at risk.

[2]

Not Calculated, fewer than 5 subjects at risk

16. Secondary Outcome

Title	Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Overall Survival Rate (OSR)
Description	The proportion of subjects surviving to time t, where t is a specific length of time, eg, 12 months, which was determined by the available data for final analysis and was documented in the DPP. The proportion was calculated by the product-limit method (Kaplan-Meier estimate), which takes into account censored data. The overall survival rate (OSR) for a subject was defined as the time from the date of first dose of study medication to the date of death for any cause. A subject who had not died was censored at last known date alive
Time Frame	2 years from first dose of treatment; Assessed up to September 2017

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	N3 60M Naive	N3 60M PROG	N1 60M + I3 90M	N1 30M + I3 30M NON-BM	N3 30M NON-BM	N1 30M + I3 30M BM	N3 30M BM	N1 + I3 NON-BM	N3 NAIVE	All N3	N1 + I3	Total
Arm/Group Description:	N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed;	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases	N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases	N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive	N3 = Nivolumab 3mg/kg	All combination	All treatments
Overall Number of Participants Analyzed	41	44	27	25	11	10	10	52	62	106	62	168
Median (95% Confidence Interval); Unit of Measure: Percentage of participants
3 months	92.7; (79.0 to 97.6)	90.8; (77.3 to 96.4)	85.2; (65.2 to 94.2)	100.0; (100.0 to 100.0)	90.0; (47.3 to 98.5)	90.0; (47.3 to 98.5)	80.0; (40.9 to 94.6)	92.3; (80.8 to 97.0)	90.2; (79.6 to 95.5)	90.5; (83.0 to 94.8)	91.9; (81.7 to 96.6)	91.0; (85.5 to 94.5)
6 months	85.3; (70.2 to 93.1)	78.9; (63.3 to 88.4)	81.5; (61.1 to 91.8)	100.0; (100.0 to 100.0)	90.0; (47.3 to 98.5)	90.0; (47.3 to 98.5)	80.0; (40.9 to 94.6)	90.4; (78.4 to 95.9)	85.3; (73.6 to 92.0)	82.6; (73.8 to 88.6)	90.3; (79.7 to 95.5)	85.5; (79.2 to 90.1)
9 months	75.0; (58.5 to 85.7)	71.7; (55.5 to 82.8)	81.5; (61.1 to 91.8)	88.0; (67.3 to 96.0)	90.0; (47.3 to 98.5)	90.0; (47.3 to 98.5)	68.6; (30.5 to 88.7)	84.6; (71.6 to 92.0)	76.6; (63.7 to 85.4)	74.6; (64.9 to 81.9)	85.5; (74.0 to 92.2)	78.7; (71.6 to 84.2)
12 months	72.4; (55.7 to 83.7)	64.5; (48.2 to 76.9)	77.6; (56.8 to 89.3)	88.0; (67.3 to 96.0)	80.0; (40.9 to 94.6)	90.0; (47.3 to 98.5)	68.6; (30.5 to 88.7)	82.6; (69.3 to 90.6)	73.1; (59.8 to 82.6)	69.5; (59.5 to 77.5)	83.8; (72.0 to 91.0)	74.9; (67.5 to 80.9)
24 months	51.0; (34.3 to 65.4)	46.8; (31.1 to 61.1)	69.6; (48.3 to 83.5)	58.5; (36.4 to 75.2)	58.3; (23.0 to 82.1)	77.1; (34.5 to 93.9)	NA [1]; (NA to NA)	64.2; (49.2 to 75.8)	53.1; (39.4 to 65.1)	50.5; (40.2 to 59.9)	66.5; (52.8 to 77.0)	56.6; (48.4 to 63.9)

[1]

N.C.: Not Calculated, fewer than 5 subjects at risk.

Adverse Events

Time Frame	From First dose up to 100 days after last dose of study drug, assessed up to September 2017 (approximately 59 months)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	UNPLANNED	NIV3-NAIVE	NIV3-PROG	NIV1+IPI3 P2	NIV1+IPI3 P3	NIV3-Q2W P3	IPI3-Q3W P3	NIV1+IPI3 P4	NIV3-Q2W P4
Arm/Group Description	Unplanned	Treatment Group: NIV3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive	Treatment Group: NIV3 = Nivolumab 3mg/kg; PROG = Anti-CTLA4 Progressed	Treatment Group:NIV1 = Nivolumab 1mg/kg; IPI3 = Ipilimumab 3 mg/kg; P2 = Part 2	Treatment Group: NIV1 = Nivolumab 1mg/kg; IPI3 = Ipilimumab 3 mg/kg; P3 = Part 3	Treatment Group: NIV3 = Nivolumab 3mg/kg; Q2W = every 2 weeks; P3 = Part 3	Treatment Group: IPI3 = Ipilimumab 3 mg/kg; Q3W = Every 3 weeks; P3 = Part 3	Treatment Group: NIV1 = Nivolumab 1mg/kg; IPI3 = Ipilimumab 3 mg/kg; P4 = Part 4	Treatment Group: N3 = Nivolumab 3mg/kg; Q2W = Every 2 weeks; P4 = Part 4
All-Cause Mortality
	UNPLANNED	NIV3-NAIVE	NIV3-PROG	NIV1+IPI3 P2	NIV1+IPI3 P3	NIV3-Q2W P3	IPI3-Q3W P3	NIV1+IPI3 P4	NIV3-Q2W P4
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/1 (100.00%)	26/41 (63.41%)	25/44 (56.82%)	10/27 (37.04%)	12/25 (48.00%)	4/11 (36.36%)	1/1 (100.00%)	2/10 (20.00%)	4/10 (40.00%)
Serious Adverse Events
	UNPLANNED	NIV3-NAIVE	NIV3-PROG	NIV1+IPI3 P2	NIV1+IPI3 P3	NIV3-Q2W P3	IPI3-Q3W P3	NIV1+IPI3 P4	NIV3-Q2W P4
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/1 (100.00%)	16/41 (39.02%)	16/44 (36.36%)	20/27 (74.07%)	13/25 (52.00%)	2/11 (18.18%)	1/1 (100.00%)	6/10 (60.00%)	4/10 (40.00%)
Blood and lymphatic system disorders
Anaemia † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Autoimmune haemolytic anaemia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Immune thrombocytopenic purpura † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Thrombocytopenia † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Cardiac disorders
Cardiac failure congestive † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Myocardial infarction † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Endocrine disorders
Adrenal insufficiency † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Hyperthyroidism † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Hypophysitis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Autoimmune colitis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Colitis † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	3/27 (11.11%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Constipation † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Diarrhoea † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	4/27 (14.81%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Enterocolitis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Gastrointestinal necrosis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Intra-abdominal fluid collection † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Nausea † 1	1/1 (100.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Pancreatitis † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Small intestinal obstruction † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Vomiting † 1	1/1 (100.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
General disorders
Malaise † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Non-cardiac chest pain † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Pain † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Pyrexia † 1	0/1 (0.00%)	1/41 (2.44%)	1/44 (2.27%)	3/27 (11.11%)	4/25 (16.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hepatobiliary disorders
Autoimmune hepatitis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Bile duct obstruction † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hepatitis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hepatotoxicity † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Immune system disorders
Hypersensitivity † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Infections and infestations
Clostridium difficile infection † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Liver abscess † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Meningitis † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Pneumonia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Respiratory tract infection † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Sepsis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Sinusitis † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Staphylococcal infection † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Urinary tract infection † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Injury, poisoning and procedural complications
Fall † 1	1/1 (100.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Lower limb fracture † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Investigations
Alanine aminotransferase increased † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Blood bilirubin increased † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Hepatic enzyme increased † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Lipase increased † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	1/1 (100.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Failure to thrive † 1	1/1 (100.00%)	0/41 (0.00%)	0/44 (0.00%)	2/27 (7.41%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hyperglycaemia † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hyperkalaemia † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hypokalaemia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hyponatraemia † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	2/27 (7.41%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Musculoskeletal and connective tissue disorders
Arthritis † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Bone disorder † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Flank pain † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Musculoskeletal chest pain † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Pain in extremity † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Malignant neoplasm progression † 1	0/1 (0.00%)	3/41 (7.32%)	2/44 (4.55%)	4/27 (14.81%)	2/25 (8.00%)	1/11 (9.09%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Metastases to central nervous system † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Metastatic neoplasm † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Squamous cell carcinoma † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Tumour pain † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	1/1 (100.00%)	0/10 (0.00%)	0/10 (0.00%)
Nervous system disorders
Aphasia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Dysaesthesia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Guillain-barre syndrome † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hemiparesis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Monoplegia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Nystagmus † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Paraesthesia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Seizure † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Psychiatric disorders
Confusional state † 1	1/1 (100.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Haematuria † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Renal failure † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Reproductive system and breast disorders
Pelvic pain † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Dyspnoea † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hypoxia † 1	1/1 (100.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Pneumonitis † 1	0/1 (0.00%)	1/41 (2.44%)	1/44 (2.27%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Pneumothorax † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Pulmonary embolism † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Respiratory failure † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Skin and subcutaneous tissue disorders
Rash † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Surgical and medical procedures
Brain tumour operation † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	1/11 (9.09%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Liver operation † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Vascular disorders
Hypotension † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	UNPLANNED	NIV3-NAIVE	NIV3-PROG	NIV1+IPI3 P2	NIV1+IPI3 P3	NIV3-Q2W P3	IPI3-Q3W P3	NIV1+IPI3 P4	NIV3-Q2W P4
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/1 (100.00%)	41/41 (100.00%)	44/44 (100.00%)	27/27 (100.00%)	25/25 (100.00%)	10/11 (90.91%)	1/1 (100.00%)	10/10 (100.00%)	9/10 (90.00%)
Blood and lymphatic system disorders
Anaemia † 1	0/1 (0.00%)	9/41 (21.95%)	7/44 (15.91%)	4/27 (14.81%)	5/25 (20.00%)	0/11 (0.00%)	1/1 (100.00%)	1/10 (10.00%)	2/10 (20.00%)
Haemolytic anaemia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Thrombocytopenia † 1	0/1 (0.00%)	2/41 (4.88%)	1/44 (2.27%)	2/27 (7.41%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Angina pectoris † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Palpitations † 1	0/1 (0.00%)	1/41 (2.44%)	1/44 (2.27%)	2/27 (7.41%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Tachycardia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	4/27 (14.81%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Ear and labyrinth disorders
Hypoacusis † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	2/10 (20.00%)	0/10 (0.00%)
Endocrine disorders
Adrenal insufficiency † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	2/27 (7.41%)	4/25 (16.00%)	0/11 (0.00%)	0/1 (0.00%)	3/10 (30.00%)	0/10 (0.00%)
Endocrine disorder † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Hyperthyroidism † 1	0/1 (0.00%)	1/41 (2.44%)	2/44 (4.55%)	6/27 (22.22%)	4/25 (16.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	1/10 (10.00%)
Hypophysitis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hypothyroidism † 1	1/1 (100.00%)	5/41 (12.20%)	5/44 (11.36%)	5/27 (18.52%)	4/25 (16.00%)	0/11 (0.00%)	0/1 (0.00%)	2/10 (20.00%)	1/10 (10.00%)
Eye disorders
Conjunctival oedema † 1	1/1 (100.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Dry eye † 1	0/1 (0.00%)	2/41 (4.88%)	1/44 (2.27%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	2/10 (20.00%)	1/10 (10.00%)
Eye disorder † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Eye pain † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	1/27 (3.70%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Uveitis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	1/10 (10.00%)
Vision blurred † 1	0/1 (0.00%)	2/41 (4.88%)	3/44 (6.82%)	0/27 (0.00%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	2/10 (20.00%)
Visual impairment † 1	0/1 (0.00%)	0/41 (0.00%)	2/44 (4.55%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Gastrointestinal disorders
Abdominal discomfort † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Abdominal distension † 1	0/1 (0.00%)	2/41 (4.88%)	3/44 (6.82%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Abdominal pain † 1	0/1 (0.00%)	9/41 (21.95%)	4/44 (9.09%)	7/27 (25.93%)	4/25 (16.00%)	3/11 (27.27%)	1/1 (100.00%)	0/10 (0.00%)	1/10 (10.00%)
Abdominal pain upper † 1	0/1 (0.00%)	2/41 (4.88%)	2/44 (4.55%)	1/27 (3.70%)	3/25 (12.00%)	0/11 (0.00%)	0/1 (0.00%)	2/10 (20.00%)	0/10 (0.00%)
Anal pruritus † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Constipation † 1	1/1 (100.00%)	11/41 (26.83%)	13/44 (29.55%)	7/27 (25.93%)	0/25 (0.00%)	1/11 (9.09%)	0/1 (0.00%)	1/10 (10.00%)	2/10 (20.00%)
Diarrhoea † 1	0/1 (0.00%)	13/41 (31.71%)	14/44 (31.82%)	10/27 (37.04%)	9/25 (36.00%)	4/11 (36.36%)	0/1 (0.00%)	6/10 (60.00%)	1/10 (10.00%)
Dry mouth † 1	0/1 (0.00%)	2/41 (4.88%)	6/44 (13.64%)	1/27 (3.70%)	2/25 (8.00%)	1/11 (9.09%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Dyspepsia † 1	0/1 (0.00%)	2/41 (4.88%)	4/44 (9.09%)	1/27 (3.70%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Dysphagia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	1/11 (9.09%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Flatulence † 1	0/1 (0.00%)	0/41 (0.00%)	2/44 (4.55%)	2/27 (7.41%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Gastritis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	1/11 (9.09%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Gastrointestinal haemorrhage † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Nausea † 1	1/1 (100.00%)	9/41 (21.95%)	11/44 (25.00%)	8/27 (29.63%)	12/25 (48.00%)	4/11 (36.36%)	0/1 (0.00%)	7/10 (70.00%)	2/10 (20.00%)
Stomatitis † 1	0/1 (0.00%)	3/41 (7.32%)	2/44 (4.55%)	1/27 (3.70%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Vomiting † 1	1/1 (100.00%)	4/41 (9.76%)	4/44 (9.09%)	4/27 (14.81%)	9/25 (36.00%)	1/11 (9.09%)	0/1 (0.00%)	3/10 (30.00%)	1/10 (10.00%)
General disorders
Asthenia † 1	0/1 (0.00%)	3/41 (7.32%)	1/44 (2.27%)	5/27 (18.52%)	3/25 (12.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Axillary pain † 1	1/1 (100.00%)	1/41 (2.44%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Chest pain † 1	1/1 (100.00%)	1/41 (2.44%)	1/44 (2.27%)	0/27 (0.00%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	2/10 (20.00%)
Chills † 1	0/1 (0.00%)	2/41 (4.88%)	4/44 (9.09%)	7/27 (25.93%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	2/10 (20.00%)	2/10 (20.00%)
Fatigue † 1	1/1 (100.00%)	21/41 (51.22%)	29/44 (65.91%)	14/27 (51.85%)	13/25 (52.00%)	5/11 (45.45%)	1/1 (100.00%)	6/10 (60.00%)	6/10 (60.00%)
Hernia pain † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Influenza like illness † 1	0/1 (0.00%)	4/41 (9.76%)	3/44 (6.82%)	4/27 (14.81%)	3/25 (12.00%)	1/11 (9.09%)	0/1 (0.00%)	3/10 (30.00%)	3/10 (30.00%)
Localised oedema † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	1/11 (9.09%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Malaise † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	2/27 (7.41%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Mucosal inflammation † 1	0/1 (0.00%)	3/41 (7.32%)	0/44 (0.00%)	0/27 (0.00%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Non-cardiac chest pain † 1	0/1 (0.00%)	2/41 (4.88%)	0/44 (0.00%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Oedema peripheral † 1	0/1 (0.00%)	8/41 (19.51%)	4/44 (9.09%)	4/27 (14.81%)	4/25 (16.00%)	0/11 (0.00%)	0/1 (0.00%)	3/10 (30.00%)	1/10 (10.00%)
Pain † 1	0/1 (0.00%)	3/41 (7.32%)	11/44 (25.00%)	1/27 (3.70%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	1/10 (10.00%)
Peripheral swelling † 1	0/1 (0.00%)	1/41 (2.44%)	0/44 (0.00%)	2/27 (7.41%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Pyrexia † 1	0/1 (0.00%)	10/41 (24.39%)	9/44 (20.45%)	15/27 (55.56%)	8/25 (32.00%)	3/11 (27.27%)	0/1 (0.00%)	5/10 (50.00%)	3/10 (30.00%)
Temperature intolerance † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Hepatobiliary disorders
Hepatic pain † 1	0/1 (0.00%)	0/41 (0.00%)	3/44 (6.82%)	1/27 (3.70%)	0/25 (0.00%)	2/11 (18.18%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Hypertransaminasaemia † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	2/27 (7.41%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Immune system disorders
Drug hypersensitivity † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Hypersensitivity † 1	0/1 (0.00%)	1/41 (2.44%)	1/44 (2.27%)	2/27 (7.41%)	0/25 (0.00%)	1/11 (9.09%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Infections and infestations
Cellulitis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	1/11 (9.09%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Conjunctivitis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	2/27 (7.41%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	2/10 (20.00%)	0/10 (0.00%)
Influenza † 1	0/1 (0.00%)	0/41 (0.00%)	1/44 (2.27%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Nasopharyngitis † 1	1/1 (100.00%)	3/41 (7.32%)	0/44 (0.00%)	3/27 (11.11%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)
Pneumonia † 1	0/1 (0.00%)	2/41 (4.88%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Rash pustular † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Respiratory tract infection † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	1/27 (3.70%)	1/25 (4.00%)	1/11 (9.09%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Rhinitis † 1	0/1 (0.00%)	1/41 (2.44%)	2/44 (4.55%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Sepsis † 1	0/1 (0.00%)	0/41 (0.00%)	0/44 (0.00%)	4/27 (14.81%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Sinusitis † 1	0/1 (0.00%)	2/41 (4.88%)	2/44 (4.55%)	2/27 (7.41%)	1/25 (4.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Skin infection † 1	0/1 (0.00%)	3/41 (7.32%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Upper respiratory tract infection † 1	0/1 (0.00%)	4/41 (9.76%)	4/44 (9.09%)	2/27 (7.41%)	2/25 (8.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Urinary tract infection † 1	0/1 (0.00%)	2/41 (4.88%)	2/44 (4.55%)	2/27 (7.41%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	1/10 (10.00%)	0/10 (0.00%)
Injury, poisoning and procedural complications
Contusion † 1	0/1 (0.00%)	5/41 (12.20%)	2/44 (4.55%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Fall † 1	1/1 (100.00%)	2/41 (4.88%)	1/44 (2.27%)	0/27 (0.00%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	0/10 (0.00%)
Infusion related reaction † 1	0/1 (0.00%)	1/41 (2.44%)	2/44 (4.55%)	1/27 (3.70%)	0/25 (0.00%)	0/11 (0.00%)	0/1 (0.00%)	0/10 (0.00%)	1/10 (10.00%)