A Study to Evaluate Efficacy in Subjects With Esophageal Cancer Treated With Nivolumab and Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin (CheckMate 648)

• ClinicalTrials.gov Identifier: NCT03143153
• Recruitment Status: Active, not recruiting
• First Posted: May 8, 2017
• Results First Posted: March 2, 2022
• Last Update Posted: December 4, 2023
• Sponsor: Bristol-Myers Squibb
• Collaborator: Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Bristol-Myers Squibb

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Various Advanced Cancer
• Interventions: Biological: Nivolumab; Biological: Ipilimumab; Drug: Cisplatin; Drug: Fluorouracil
• Enrollment: 970

Participant Flow

Recruitment Details
Pre-assignment Details	970 participants randomized, 936 treated.

Arm/Group Title	Arm A: Nivolumab + Ipilimumab	Arm B: Nivolumab + Chemotherapy	Arm C: Chemotherapy
Arm/Group Description	Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.	Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.	Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
Period Title: Pre-Treatment
Started [1]	325	321	324
Completed [2]	322	310	304
Not Completed	3	11	20
Reason Not Completed
Participant request to discontinue study treatment	0	0	2
Participant withdrew consent	0	1	12
Participant no longer meets study criteria	0	4	2
Other Reasons	1	2	1
Disease Progression	1	1	2
Adverse event unrelated to study drug	1	3	1
[1] Started=Randomized; [2] Completed=Treated
Period Title: Treatment
Started	322	310	304
Completed [1]	21	25	4
Not Completed	301	285	300
Reason Not Completed
Disease progression	174	184	193
Study drug toxicity	59	33	40
Death	5	3	4
Adverse event unrelated to study drug	19	28	12
Participant request to discontinue study treatment	13	15	20
Participant withdrew consent	3	4	12
Pregnancy	1	0	0
Maximum clinical benefit	1	3	4
Completed treatment as per Protocol	13	8	0
Other reasons	12	7	15
Not reported	1	0	0
[1] Completed=continuing treatment

Baseline Characteristics

Arm/Group Title		Arm A: Nivolumab + Ipilimumab	Arm B: Nivolumab + Chemotherapy	Arm C: Chemotherapy	Total
Arm/Group Description		Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.	Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.	Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.	Total of all reporting groups
Overall Number of Baseline Participants		325	321	324	970
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	325 participants	321 participants	324 participants	970 participants
		62.2 (9.1)	63.1 (9.2)	63.3 (8.7)	62.9 (9.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	325 participants	321 participants	324 participants	970 participants
	Female	56 17.2%	68 21.2%	49 15.1%	173 17.8%
	Male	269 82.8%	253 78.8%	275 84.9%	797 82.2%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	325 participants	321 participants	324 participants	970 participants
White		79	85	84	248
Black or African American		4	1	6	11
American Indian or Alaska Native		1	2	1	4
Asian Indian		1	4	3	8
Chinese		71	74	70	215
Japanese		131	126	137	394
Asian Other		28	23	17	68
Other		10	6	6	22

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) in Participants With Tumor Cell PD-L1
Description	Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.
Time Frame	From the date of randomization to up to the date of death (up to approximately 20 months)

Outcome Measure Data

Analysis Population Description

All randomized PD-L1 expressing participants

Arm/Group Title	Arm A: Nivolumab + Ipilimumab	Arm B: Nivolumab + Chemotherapy	Arm C: Chemotherapy
Arm/Group Description:	Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.	Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.	Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
Overall Number of Participants Analyzed	158	158	157
Median (95% Confidence Interval); Unit of Measure: Months
	13.70; (11.24 to 17.02)	15.44; (11.93 to 19.52)	9.07; (7.69 to 9.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivolumab + Ipilimumab, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0010
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 98.6%; 0.46 to 0.90
	Estimation Comments	Stratified Cox proportional hazard model.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivolumab + Ipilimumab, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0010
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.84
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm B: Nivolumab + Chemotherapy, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 99.5%; 0.37 to 0.80
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm B: Nivolumab + Chemotherapy, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.41 to 0.71
	Estimation Comments	Stratified Cox proportional hazard model

2. Primary Outcome

Title	Progression-free Survival (PFS) as Assessed by BICR in Participants With Tumor Cell PD-L1
Description	Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.
Time Frame	From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 9 months)

Outcome Measure Data

Analysis Population Description

All randomized PD-L1 expressing participants

Arm/Group Title	Arm A: Nivolumab + Ipilimumab	Arm B: Nivolumab + Chemotherapy	Arm C: Chemotherapy
Arm/Group Description:	Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.	Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.	Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
Overall Number of Participants Analyzed	158	158	157
Median (95% Confidence Interval); Unit of Measure: Months
	4.04; (2.40 to 4.93)	6.93; (5.68 to 8.34)	4.44; (2.89 to 5.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivolumab + Ipilimumab, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8958
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 98.5%; 0.73 to 1.43
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivolumab + Ipilimumab, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8958
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.34
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm B: Nivolumab + Chemotherapy, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0023
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 98.5%; 0.46 to 0.92
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm B: Nivolumab + Chemotherapy, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0023
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.86
	Estimation Comments	Stratified Cox proportional hazard model

3. Secondary Outcome

Title	Overall Survival (OS) in All Randomized Participants
Description	Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.
Time Frame	From the date of randomization to up to the date of death (up to approximately 16 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Arm A: Nivolumab + Ipilimumab	Arm B: Nivolumab + Chemotherapy	Arm C: Chemotherapy
Arm/Group Description:	Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.	Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.	Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
Overall Number of Participants Analyzed	325	321	324
Median (95% Confidence Interval); Unit of Measure: Months
	12.75; (11.27 to 15.47)	13.21; (11.14 to 15.70)	10.71; (9.40 to 11.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivolumab + Ipilimumab, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0110
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2), PD-L1 status (>= 1% vs. < 1% or indeterminate) as recorded in IRT
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	95%; 0.65 to 0.95
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivolumab + Ipilimumab, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0110
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2), PD-L1 status (>= 1% vs. < 1% or indeterminate) as recorded in IRT.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	98.2%; 0.62 to 0.98
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm B: Nivolumab + Chemotherapy, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0021
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2), PD-L1 status (>= 1% vs. < 1% or indeterminate) as recorded in IRT
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	99.1%; 0.58 to 0.96
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm B: Nivolumab + Chemotherapy, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0021
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2), PD-L1 status (>= 1% vs. < 1% or indeterminate) as recorded in IRT
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.61 to 0.90
	Estimation Comments	Stratified Cox proportional hazard model

4. Secondary Outcome

Title	Progression-free Survival (PFS) in All Randomized Participants as Assessed by BICR
Description	Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.
Time Frame	From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 7 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Arm A: Nivolumab + Ipilimumab	Arm B: Nivolumab + Chemotherapy	Arm C: Chemotherapy
Arm/Group Description:	Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.	Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.	Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
Overall Number of Participants Analyzed	325	321	324
Median (95% Confidence Interval); Unit of Measure: Months
	2.92; (2.66 to 4.17)	5.82; (5.55 to 7.00)	5.59; (4.27 to 5.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivolumab + Ipilimumab, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 1.04 to 1.52
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm B: Nivolumab + Chemotherapy, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0355
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2), PD-L1 status (>= 1% vs. < 1% or indeterminate) as recorded in IRT
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.99
	Estimation Comments	Stratified Cox proportional hazard model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm B: Nivolumab + Chemotherapy, Arm C: Chemotherapy
	Comments	Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0355
	Comments	Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2), PD-L1 status (>= 1% vs. < 1% or indeterminate) as recorded in IRT
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 98.5%; 0.64 to 1.04
	Estimation Comments	Stratified Cox proportional hazard model

5. Secondary Outcome

Title	Objective Response Rate (ORR) as Assessed by BICR
Description	Objective response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation as determined by BICR, recorded between the date of randomization and the date of objectively documented progression (per RECIST 1.1) or the date of subsequent anti-cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions. Complete response is defined as the disappearance of all target lesions and the reduction of any pathological lymph nodes to <10 mm.
Time Frame	From the date of randomization to up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to 40 months)

Outcome Measure Data

Analysis Population Description

All randomized PD-L1 expressing participants and all randomized participants

Arm/Group Title		Arm A: Nivolumab + Ipilimumab	Arm B: Nivolumab + Chemotherapy	Arm C: Chemotherapy
Arm/Group Description:		Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.	Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.	Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
Overall Number of Participants Analyzed		325	321	324
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
Participants with baseline PD-L1 status < 1%	Number Analyzed	164 participants	163 participants	166 participants
		20.1; (14.3 to 27.1)	41.7; (34.1 to 49.7)	33.7; (26.6 to 41.5)
Participants with baseline PD-L1 status >= 1%	Number Analyzed	158 participants	158 participants	156 participants
		35.4; (28.0 to 43.4)	53.2; (45.1 to 61.1)	19.9; (13.9 to 27.0)
Participants with baseline PD-L1 status < 5%	Number Analyzed	202 participants	201 participants	207 participants
		22.3; (16.7 to 28.6)	44.8; (37.8 to 51.9)	30.9; (24.7 to 37.7)
Participants with baseline PD-L1 status >= 5%	Number Analyzed	120 participants	120 participants	115 participants
		36.7; (28.1 to 45.9)	51.7; (42.4 to 60.9)	20.0; (13.1 to 28.5)
Participants with baseline PD-L1 status < 10%	Number Analyzed	219 participants	219 participants	225 participants
		23.3; (17.9 to 29.5)	46.1; (39.4 to 53.0)	29.3; (23.5 to 35.8)
Participants with baseline PD-L1 status >= 10%	Number Analyzed	103 participants	102 participants	97 participants
		36.9; (27.6 to 47.0)	50.0; (39.9 to 60.1)	21.6; (13.9 to 31.2)
Participants with baseline PD-L1 status indeterminate, not evaluable, or missing	Number Analyzed	3 participants	0 participants	2 participants
		33.3; (0.8 to 90.6)		0.0; (0.0 to 84.2)
All randomized participants	Number Analyzed	325 participants	321 participants	324 participants
		27.7; (22.9 to 32.9)	47.4; (41.8 to 53.0)	26.9; (22.1 to 32.0)

Adverse Events

Time Frame	From first dose to 100 days post last dose, up to 43 months
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg	Nivolumab 240 mg + Chemotherapy	Chemotherapy
Arm/Group Description	Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.	Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.	Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
All-Cause Mortality
	Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg	Nivolumab 240 mg + Chemotherapy	Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	215/322 (66.77%)	200/310 (64.52%)	224/304 (73.68%)
Serious Adverse Events
	Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg	Nivolumab 240 mg + Chemotherapy	Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	237/322 (73.60%)	217/310 (70.00%)	172/304 (56.58%)
Blood and lymphatic system disorders
Anaemia † 1	5/322 (1.55%)	5/310 (1.61%)	6/304 (1.97%)
Disseminated intravascular coagulation † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Febrile bone marrow aplasia † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Febrile neutropenia † 1	6/322 (1.86%)	6/310 (1.94%)	5/304 (1.64%)
Immune thrombocytopenia † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Leukocytosis † 1	1/322 (0.31%)	0/310 (0.00%)	1/304 (0.33%)
Leukopenia † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Lymphadenopathy † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Myelosuppression † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Neutropenia † 1	0/322 (0.00%)	2/310 (0.65%)	1/304 (0.33%)
Pancytopenia † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Splenic haematoma † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Thrombocytopenia † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Cardiac disorders
Acute myocardial infarction † 1	1/322 (0.31%)	0/310 (0.00%)	2/304 (0.66%)
Angina pectoris † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Arrhythmia † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Arteriospasm coronary † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Atrial fibrillation † 1	1/322 (0.31%)	0/310 (0.00%)	3/304 (0.99%)
Cardiac arrest † 1	0/322 (0.00%)	2/310 (0.65%)	0/304 (0.00%)
Cardiac failure congestive † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Palpitations † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Pericardial effusion † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Supraventricular tachycardia † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Ventricular fibrillation † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Endocrine disorders
Adrenal insufficiency † 1	8/322 (2.48%)	2/310 (0.65%)	0/304 (0.00%)
Adrenocorticotropic hormone deficiency † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Endocrine disorder † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Hypercalcaemia of malignancy † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Hyperthyroidism † 1	2/322 (0.62%)	1/310 (0.32%)	0/304 (0.00%)
Hypophysitis † 1	6/322 (1.86%)	0/310 (0.00%)	0/304 (0.00%)
Hypopituitarism † 1	6/322 (1.86%)	1/310 (0.32%)	0/304 (0.00%)
Hypothyroidism † 1	3/322 (0.93%)	1/310 (0.32%)	0/304 (0.00%)
Inappropriate antidiuretic hormone secretion † 1	1/322 (0.31%)	0/310 (0.00%)	1/304 (0.33%)
Secondary adrenocortical insufficiency † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Thyroiditis † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Eye disorders
Cataract † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Eye pain † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Retinal detachment † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Uveitis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Vogt-Koyanagi-Harada disease † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Gastrointestinal disorders
Abdominal distension † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Abdominal pain † 1	1/322 (0.31%)	3/310 (0.97%)	2/304 (0.66%)
Abdominal pain lower † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Abdominal pain upper † 1	1/322 (0.31%)	1/310 (0.32%)	2/304 (0.66%)
Aorto-oesophageal fistula † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Ascites † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Colitis † 1	4/322 (1.24%)	5/310 (1.61%)	0/304 (0.00%)
Constipation † 1	2/322 (0.62%)	2/310 (0.65%)	1/304 (0.33%)
Diaphragmatic hernia † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Diarrhoea † 1	5/322 (1.55%)	6/310 (1.94%)	3/304 (0.99%)
Duodenal ulcer † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Dysphagia † 1	12/322 (3.73%)	20/310 (6.45%)	16/304 (5.26%)
Enteritis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Enterocolitis † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Gastric fistula † 1	1/322 (0.31%)	2/310 (0.65%)	0/304 (0.00%)
Gastric perforation † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Gastritis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Gastrointestinal haemorrhage † 1	6/322 (1.86%)	1/310 (0.32%)	2/304 (0.66%)
Gastrointestinal obstruction † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Haematemesis † 1	2/322 (0.62%)	0/310 (0.00%)	2/304 (0.66%)
Haematochezia † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Ileus † 1	1/322 (0.31%)	0/310 (0.00%)	1/304 (0.33%)
Ileus paralytic † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Inguinal hernia † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Intestinal obstruction † 1	0/322 (0.00%)	1/310 (0.32%)	2/304 (0.66%)
Mechanical ileus † 1	1/322 (0.31%)	0/310 (0.00%)	1/304 (0.33%)
Melaena † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Nausea † 1	2/322 (0.62%)	4/310 (1.29%)	5/304 (1.64%)
Odynophagia † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Oesophageal fistula † 1	0/322 (0.00%)	0/310 (0.00%)	3/304 (0.99%)
Oesophageal haemorrhage † 1	1/322 (0.31%)	1/310 (0.32%)	1/304 (0.33%)
Oesophageal mass † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Oesophageal motility disorder † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Oesophageal obstruction † 1	3/322 (0.93%)	3/310 (0.97%)	5/304 (1.64%)
Oesophageal pain † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Oesophageal perforation † 1	1/322 (0.31%)	2/310 (0.65%)	1/304 (0.33%)
Oesophageal stenosis † 1	3/322 (0.93%)	9/310 (2.90%)	13/304 (4.28%)
Oesophageal-pulmonary fistula † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Oesophagomediastinal fistula † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Pancreatitis † 1	4/322 (1.24%)	0/310 (0.00%)	0/304 (0.00%)
Pancreatitis acute † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Pneumatosis intestinalis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Rectal perforation † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Small intestinal haemorrhage † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Small intestinal obstruction † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Stomatitis † 1	1/322 (0.31%)	5/310 (1.61%)	0/304 (0.00%)
Upper gastrointestinal haemorrhage † 1	3/322 (0.93%)	2/310 (0.65%)	2/304 (0.66%)
Vomiting † 1	4/322 (1.24%)	4/310 (1.29%)	12/304 (3.95%)
General disorders
Asthenia † 1	5/322 (1.55%)	2/310 (0.65%)	1/304 (0.33%)
Catheter site discharge † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Chest pain † 1	1/322 (0.31%)	2/310 (0.65%)	0/304 (0.00%)
Complication associated with device † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Death † 1	5/322 (1.55%)	2/310 (0.65%)	1/304 (0.33%)
Disease progression † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Fatigue † 1	2/322 (0.62%)	3/310 (0.97%)	1/304 (0.33%)
Feeling cold † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
General physical health deterioration † 1	2/322 (0.62%)	1/310 (0.32%)	1/304 (0.33%)
Malaise † 1	2/322 (0.62%)	1/310 (0.32%)	0/304 (0.00%)
Mucosal inflammation † 1	0/322 (0.00%)	2/310 (0.65%)	2/304 (0.66%)
Multiple organ dysfunction syndrome † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Nodule † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Non-cardiac chest pain † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Oedema peripheral † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Pain † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Performance status decreased † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Polyp † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Pyrexia † 1	14/322 (4.35%)	7/310 (2.26%)	7/304 (2.30%)
Sudden death † 1	1/322 (0.31%)	2/310 (0.65%)	2/304 (0.66%)
Hepatobiliary disorders
Autoimmune hepatitis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Bile duct stone † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Biliary obstruction † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Cholangitis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Cholecystitis † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Cholecystitis acute † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Hepatic failure † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Hepatic function abnormal † 1	9/322 (2.80%)	1/310 (0.32%)	1/304 (0.33%)
Hepatitis † 1	3/322 (0.93%)	0/310 (0.00%)	0/304 (0.00%)
Immune-mediated hepatitis † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Jaundice cholestatic † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Immune system disorders
Anaphylactic shock † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Drug hypersensitivity † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Hypersensitivity † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Infections and infestations
Appendicitis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Bacteraemia † 1	2/322 (0.62%)	0/310 (0.00%)	1/304 (0.33%)
Bacterial infection † 1	1/322 (0.31%)	0/310 (0.00%)	1/304 (0.33%)
COVID-19 pneumonia † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Catheter site infection † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Cystitis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Device related infection † 1	0/322 (0.00%)	2/310 (0.65%)	3/304 (0.99%)
Encephalitis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Enterocolitis infectious † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Gastroenteritis bacterial † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
H1N1 influenza † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Infection † 1	0/322 (0.00%)	2/310 (0.65%)	1/304 (0.33%)
Large intestine infection † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Lower respiratory tract infection † 1	2/322 (0.62%)	1/310 (0.32%)	1/304 (0.33%)
Lung abscess † 1	1/322 (0.31%)	1/310 (0.32%)	1/304 (0.33%)
Lymph gland infection † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Mediastinitis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Meningitis viral † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Meningoencephalitis bacterial † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Neutropenic sepsis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Oral infection † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Otitis media † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Otitis media acute † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Parotitis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Peritonitis † 1	0/322 (0.00%)	0/310 (0.00%)	3/304 (0.99%)
Pharyngitis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Pneumonia † 1	31/322 (9.63%)	33/310 (10.65%)	20/304 (6.58%)
Pneumonia bacterial † 1	4/322 (1.24%)	0/310 (0.00%)	2/304 (0.66%)
Pneumonia pseudomonal † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Postoperative wound infection † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Pulmonary sepsis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Respiratory tract infection † 1	0/322 (0.00%)	2/310 (0.65%)	0/304 (0.00%)
Sepsis † 1	4/322 (1.24%)	3/310 (0.97%)	3/304 (0.99%)
Septic shock † 1	1/322 (0.31%)	0/310 (0.00%)	1/304 (0.33%)
Stoma site cellulitis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Stoma site infection † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Upper respiratory tract infection † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Urethritis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Urinary tract infection † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Urosepsis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Vascular device infection † 1	1/322 (0.31%)	0/310 (0.00%)	2/304 (0.66%)
Viral infection † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Wound infection † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Injury, poisoning and procedural complications
Anastomotic leak † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Atrio-oesophageal fistula † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Brain contusion † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Fall † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Fracture † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Gastrointestinal stoma complication † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Heat illness † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Humerus fracture † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Infusion related reaction † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Overdose † 1	5/322 (1.55%)	0/310 (0.00%)	1/304 (0.33%)
Radiation oesophagitis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Stoma site extravasation † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Subdural haematoma † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Tracheal obstruction † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Investigations
Adjusted calcium increased † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Alanine aminotransferase increased † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Anticoagulation drug level above therapeutic † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Aspartate aminotransferase increased † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Blood calcium increased † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Blood creatine phosphokinase increased † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Blood creatinine increased † 1	3/322 (0.93%)	2/310 (0.65%)	1/304 (0.33%)
Blood sodium decreased † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Blood thyroid stimulating hormone increased † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
C-reactive protein increased † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Cortisol decreased † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Electrocardiogram Q wave abnormal † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Haemoglobin decreased † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Lipase increased † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Liver function test increased † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Neutrophil count decreased † 1	1/322 (0.31%)	4/310 (1.29%)	1/304 (0.33%)
Platelet count decreased † 1	0/322 (0.00%)	2/310 (0.65%)	2/304 (0.66%)
Transaminases increased † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Urine output decreased † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
White blood cell count decreased † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Metabolism and nutrition disorders
Cachexia † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Decreased appetite † 1	9/322 (2.80%)	4/310 (1.29%)	7/304 (2.30%)
Dehydration † 1	8/322 (2.48%)	4/310 (1.29%)	6/304 (1.97%)
Diabetes mellitus † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Diabetic ketoacidosis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Electrolyte imbalance † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Fulminant type 1 diabetes mellitus † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Gout † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Hypercalcaemia † 1	5/322 (1.55%)	4/310 (1.29%)	4/304 (1.32%)
Hyperglycaemia † 1	3/322 (0.93%)	0/310 (0.00%)	1/304 (0.33%)
Hyperglycaemic hyperosmolar nonketotic syndrome † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Hyperkalaemia † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Hypernatraemia † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Hypoalbuminaemia † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Hypocalcaemia † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Hypoglycaemia † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Hypokalaemia † 1	1/322 (0.31%)	4/310 (1.29%)	2/304 (0.66%)
Hyponatraemia † 1	6/322 (1.86%)	4/310 (1.29%)	4/304 (1.32%)
Hypophagia † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Malnutrition † 1	1/322 (0.31%)	1/310 (0.32%)	1/304 (0.33%)
Type 1 diabetes mellitus † 1	2/322 (0.62%)	2/310 (0.65%)	0/304 (0.00%)
Musculoskeletal and connective tissue disorders
Arthritis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Back pain † 1	2/322 (0.62%)	1/310 (0.32%)	0/304 (0.00%)
Gouty arthritis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Immune-mediated arthritis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Muscular weakness † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Myositis † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Osteoarthritis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Osteolysis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Rhabdomyolysis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Rheumatoid arthritis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Spinal stenosis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adult T-cell lymphoma/leukaemia † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Benign neoplasm † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Cancer pain † 1	3/322 (0.93%)	2/310 (0.65%)	1/304 (0.33%)
Colorectal cancer † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Hypopharyngeal cancer † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Lipoma † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Malignant ascites † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Malignant neoplasm progression † 1	59/322 (18.32%)	56/310 (18.06%)	62/304 (20.39%)
Metastases to bone marrow † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Metastases to central nervous system † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Metastases to kidney † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Metastases to meninges † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Metastatic squamous cell carcinoma † 1	0/322 (0.00%)	2/310 (0.65%)	0/304 (0.00%)
Oesophageal carcinoma † 1	2/322 (0.62%)	2/310 (0.65%)	1/304 (0.33%)
Rectal adenoma † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Tumour compression † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Tumour fistulisation † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Tumour haemorrhage † 1	0/322 (0.00%)	0/310 (0.00%)	3/304 (0.99%)
Tumour pain † 1	1/322 (0.31%)	0/310 (0.00%)	4/304 (1.32%)
Nervous system disorders
Brain stem haemorrhage † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Cerebral infarction † 1	2/322 (0.62%)	0/310 (0.00%)	1/304 (0.33%)
Cerebral ischaemia † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Cerebrovascular accident † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Facial paralysis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Haemorrhage intracranial † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Haemorrhagic stroke † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Hydrocephalus † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Immune-mediated encephalitis † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Immune-mediated encephalopathy † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Peripheral sensory neuropathy † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Presyncope † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Seizure † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Spinal cord compression † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Stupor † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Subdural hygroma † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Syncope † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Pregnancy, puerperium and perinatal conditions
Pregnancy † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Product Issues
Device breakage † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Device dislocation † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Device leakage † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Device occlusion † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Patient-device incompatibility † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Psychiatric disorders
Assisted suicide † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Confusional state † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Delirium † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Depression † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Disorientation † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Pressure of speech † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	2/322 (0.62%)	9/310 (2.90%)	4/304 (1.32%)
Haematuria † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Hydronephrosis † 1	1/322 (0.31%)	1/310 (0.32%)	1/304 (0.33%)
Renal failure † 1	0/322 (0.00%)	2/310 (0.65%)	2/304 (0.66%)
Urinary retention † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Respiratory, thoracic and mediastinal disorders
Acquired tracheo-oesophageal fistula † 1	1/322 (0.31%)	2/310 (0.65%)	0/304 (0.00%)
Acute respiratory distress syndrome † 1	2/322 (0.62%)	0/310 (0.00%)	0/304 (0.00%)
Acute respiratory failure † 1	1/322 (0.31%)	1/310 (0.32%)	1/304 (0.33%)
Aspiration † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Atelectasis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Bronchial obstruction † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Bronchostenosis † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Chronic obstructive pulmonary disease † 1	1/322 (0.31%)	1/310 (0.32%)	0/304 (0.00%)
Dyspnoea † 1	5/322 (1.55%)	2/310 (0.65%)	2/304 (0.66%)
Epistaxis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Haemoptysis † 1	0/322 (0.00%)	0/310 (0.00%)	2/304 (0.66%)
Hiccups † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Interstitial lung disease † 1	5/322 (1.55%)	2/310 (0.65%)	2/304 (0.66%)
Lung disorder † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Mediastinal disorder † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Obstructive airways disorder † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Oesophagobronchial fistula † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Pleural effusion † 1	4/322 (1.24%)	5/310 (1.61%)	1/304 (0.33%)
Pneumomediastinum † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Pneumonia aspiration † 1	12/322 (3.73%)	5/310 (1.61%)	8/304 (2.63%)
Pneumonitis † 1	13/322 (4.04%)	6/310 (1.94%)	1/304 (0.33%)
Pulmonary embolism † 1	2/322 (0.62%)	2/310 (0.65%)	3/304 (0.99%)
Pulmonary thrombosis † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Respiratory failure † 1	1/322 (0.31%)	5/310 (1.61%)	1/304 (0.33%)
Stridor † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Tracheal fistula † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Tracheal stenosis † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Skin and subcutaneous tissue disorders
Drug eruption † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Erythema multiforme † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Rash † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Rash maculo-papular † 1	3/322 (0.93%)	0/310 (0.00%)	0/304 (0.00%)
Subcutaneous emphysema † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Surgical and medical procedures
Jejunostomy † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Oesophageal operation † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Vascular disorders
Aortic dissection † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Deep vein thrombosis † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Embolism † 1	2/322 (0.62%)	1/310 (0.32%)	0/304 (0.00%)
Haematoma † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Hypertension † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Hypertensive crisis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Hypotension † 1	2/322 (0.62%)	1/310 (0.32%)	3/304 (0.99%)
Hypovolaemic shock † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Internal haemorrhage † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Orthostatic hypotension † 1	0/322 (0.00%)	1/310 (0.32%)	1/304 (0.33%)
Poor venous access † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
Shock † 1	0/322 (0.00%)	0/310 (0.00%)	2/304 (0.66%)
Shock haemorrhagic † 1	1/322 (0.31%)	0/310 (0.00%)	0/304 (0.00%)
Subclavian vein thrombosis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Thrombophlebitis † 1	0/322 (0.00%)	1/310 (0.32%)	0/304 (0.00%)
Venous thrombosis † 1	0/322 (0.00%)	0/310 (0.00%)	1/304 (0.33%)
1 Term from vocabulary, 23.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg	Nivolumab 240 mg + Chemotherapy	Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	301/322 (93.48%)	307/310 (99.03%)	288/304 (94.74%)
Blood and lymphatic system disorders
Anaemia † 1	82/322 (25.47%)	151/310 (48.71%)	107/304 (35.20%)
Neutropenia † 1	5/322 (1.55%)	36/310 (11.61%)	23/304 (7.57%)
Endocrine disorders
Hyperthyroidism † 1	20/322 (6.21%)	7/310 (2.26%)	1/304 (0.33%)
Hypothyroidism † 1	44/322 (13.66%)	21/310 (6.77%)	1/304 (0.33%)
Gastrointestinal disorders
Abdominal pain † 1	22/322 (6.83%)	22/310 (7.10%)	18/304 (5.92%)
Abdominal pain upper † 1	16/322 (4.97%)	20/310 (6.45%)	13/304 (4.28%)
Constipation † 1	83/322 (25.78%)	140/310 (45.16%)	137/304 (45.07%)
Diarrhoea † 1	84/322 (26.09%)	96/310 (30.97%)	63/304 (20.72%)
Dysphagia † 1	35/322 (10.87%)	39/310 (12.58%)	30/304 (9.87%)
Nausea † 1	87/322 (27.02%)	204/310 (65.81%)	172/304 (56.58%)
Stomatitis † 1	33/322 (10.25%)	99/310 (31.94%)	75/304 (24.67%)
Vomiting † 1	52/322 (16.15%)	74/310 (23.87%)	60/304 (19.74%)
General disorders
Asthenia † 1	24/322 (7.45%)	22/310 (7.10%)	26/304 (8.55%)
Fatigue † 1	53/322 (16.46%)	82/310 (26.45%)	63/304 (20.72%)
Infusion site extravasation † 1	6/322 (1.86%)	15/310 (4.84%)	21/304 (6.91%)
Malaise † 1	26/322 (8.07%)	58/310 (18.71%)	55/304 (18.09%)
Mucosal inflammation † 1	5/322 (1.55%)	36/310 (11.61%)	30/304 (9.87%)
Oedema peripheral † 1	31/322 (9.63%)	45/310 (14.52%)	25/304 (8.22%)
Pyrexia † 1	76/322 (23.60%)	62/310 (20.00%)	48/304 (15.79%)
Hepatobiliary disorders
Hepatic function abnormal † 1	17/322 (5.28%)	3/310 (0.97%)	1/304 (0.33%)
Infections and infestations
Pneumonia † 1	35/322 (10.87%)	31/310 (10.00%)	29/304 (9.54%)
Investigations
Alanine aminotransferase increased † 1	45/322 (13.98%)	26/310 (8.39%)	13/304 (4.28%)
Aspartate aminotransferase increased † 1	47/322 (14.60%)	28/310 (9.03%)	12/304 (3.95%)
Blood alkaline phosphatase increased † 1	19/322 (5.90%)	22/310 (7.10%)	10/304 (3.29%)
Blood creatinine increased † 1	12/322 (3.73%)	42/310 (13.55%)	39/304 (12.83%)
Creatinine renal clearance decreased † 1	0/322 (0.00%)	20/310 (6.45%)	9/304 (2.96%)
Lymphocyte count decreased † 1	8/322 (2.48%)	16/310 (5.16%)	9/304 (2.96%)
Neutrophil count decreased † 1	10/322 (3.11%)	75/310 (24.19%)	61/304 (20.07%)
Platelet count decreased † 1	12/322 (3.73%)	46/310 (14.84%)	36/304 (11.84%)
Weight decreased † 1	41/322 (12.73%)	40/310 (12.90%)	35/304 (11.51%)
Weight increased † 1	5/322 (1.55%)	23/310 (7.42%)	14/304 (4.61%)
White blood cell count decreased † 1	12/322 (3.73%)	58/310 (18.71%)	41/304 (13.49%)
Metabolism and nutrition disorders
Decreased appetite † 1	69/322 (21.43%)	160/310 (51.61%)	155/304 (50.99%)
Hypercalcaemia † 1	12/322 (3.73%)	20/310 (6.45%)	9/304 (2.96%)
Hyperkalaemia † 1	12/322 (3.73%)	20/310 (6.45%)	22/304 (7.24%)
Hypoalbuminaemia † 1	34/322 (10.56%)	25/310 (8.06%)	20/304 (6.58%)
Hypocalcaemia † 1	7/322 (2.17%)	17/310 (5.48%)	5/304 (1.64%)
Hypokalaemia † 1	32/322 (9.94%)	44/310 (14.19%)	30/304 (9.87%)
Hyponatraemia † 1	31/322 (9.63%)	54/310 (17.42%)	36/304 (11.84%)
Hypophosphataemia † 1	13/322 (4.04%)	17/310 (5.48%)	4/304 (1.32%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	24/322 (7.45%)	18/310 (5.81%)	14/304 (4.61%)
Back pain † 1	20/322 (6.21%)	10/310 (3.23%)	16/304 (5.26%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	18/322 (5.59%)	14/310 (4.52%)	19/304 (6.25%)
Nervous system disorders
Dizziness † 1	15/322 (4.66%)	17/310 (5.48%)	29/304 (9.54%)
Dysgeusia † 1	10/322 (3.11%)	23/310 (7.42%)	19/304 (6.25%)
Headache † 1	26/322 (8.07%)	27/310 (8.71%)	16/304 (5.26%)
Neuropathy peripheral † 1	2/322 (0.62%)	22/310 (7.10%)	15/304 (4.93%)
Peripheral sensory neuropathy † 1	5/322 (1.55%)	31/310 (10.00%)	28/304 (9.21%)
Psychiatric disorders
Insomnia † 1	32/322 (9.94%)	54/310 (17.42%)	40/304 (13.16%)
Renal and urinary disorders
Renal impairment † 1	2/322 (0.62%)	11/310 (3.55%)	17/304 (5.59%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	40/322 (12.42%)	43/310 (13.87%)	37/304 (12.17%)
Dyspnoea † 1	23/322 (7.14%)	13/310 (4.19%)	11/304 (3.62%)
Hiccups † 1	12/322 (3.73%)	53/310 (17.10%)	63/304 (20.72%)
Pneumonitis † 1	16/322 (4.97%)	19/310 (6.13%)	6/304 (1.97%)
Skin and subcutaneous tissue disorders
Alopecia † 1	9/322 (2.80%)	42/310 (13.55%)	42/304 (13.82%)
Dry skin † 1	17/322 (5.28%)	13/310 (4.19%)	12/304 (3.95%)
Pruritus † 1	59/322 (18.32%)	37/310 (11.94%)	19/304 (6.25%)
Rash † 1	74/322 (22.98%)	42/310 (13.55%)	21/304 (6.91%)
Rash maculo-papular † 1	18/322 (5.59%)	8/310 (2.58%)	3/304 (0.99%)
Vascular disorders
Hypertension † 1	9/322 (2.80%)	24/310 (7.74%)	22/304 (7.24%)
Hypotension † 1	11/322 (3.42%)	13/310 (4.19%)	16/304 (5.26%)
1 Term from vocabulary, 23.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

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

Results Point of Contact

• Name/Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb
• Phone: Please email
• EMail: Clinical.Trails@bms.com

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

Kato K, Doki Y, Ogata T, Motoyama S, Kawakami H, Ueno M, Kojima T, Shirakawa Y, Okada M, Ishihara R, Kubota Y, Amaya-Chanaga C, Chen T, Matsumura Y, Kitagawa Y. First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). Esophagus. 2023 Apr;20(2):291-301. doi: 10.1007/s10388-022-00970-1. Epub 2022 Nov 19.

Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. doi: 10.1056/NEJMoa2111380.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT03143153
• Other Study ID Numbers: CA209-648; 2016-001514-20 ( EudraCT Number )
• First Submitted: May 4, 2017
• First Posted: May 8, 2017
• Results First Submitted: January 11, 2022
• Results First Posted: March 2, 2022
• Last Update Posted: December 4, 2023