Study of Nivolumab in Combination With Ipilimumab Compared to the Standard of Care (Extreme Regimen) as First Line Treatment in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (CheckMate 651)

• ClinicalTrials.gov Identifier: NCT02741570
• Recruitment Status: Completed
• First Posted: April 18, 2016
• Results First Posted: May 3, 2022
• Last Update Posted: October 20, 2022
• 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: Head and Neck Cancer
• Interventions: Biological: Nivolumab; Biological: Ipilimumab; Drug: Cetuximab/Erbitux; Drug: Cisplatin/Platinol; Drug: Carboplatin/Paraplatin; Drug: Fluorouracil/Adrucil
• Enrollment: 947

Participant Flow

Recruitment Details
Pre-assignment Details	947 participants randomized to receive study treatment. 909 participants received study treatment.

Arm/Group Title	Nivolumab + Ipilimumab	EXTREME Regimen
Arm/Group Description	Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.	Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.
Period Title: Pre-Treatment Period
Started	472	475
Completed [1]	468	441
Not Completed	4	34
Reason Not Completed
Other reasons	0	3
Participant no longer meets study criteria	3	6
Poor/non-compliance	0	1
Lost to Follow-up	0	2
Participant withdrew consent	0	18
Participant request to discontinue study treatment	0	2
Adverse event unrelated to study drug	1	0
Death	0	1
Disease progression	0	1
[1] Continuing into treatment period
Period Title: Treatment Period
Started	468	441
Completed [1]	0	7
Not Completed	468	434
Reason Not Completed
Other reasons	47	8
Poor/non-compliance	0	1
Maximum clinical benefit	3	5
Lost to Follow-up	1	3
Participant withdrew consent	9	13
Participant request to discontinue treatment	8	23
Adverse event unrelated to study drug	41	25
Death	9	7
Study drug toxicity	55	45
Disease progression	295	304
[1] Participants continuing in the treatment period

Baseline Characteristics

Arm/Group Title		Nivolumab + Ipilimumab	EXTREME Regimen	Total
Arm/Group Description		Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.	Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.	Total of all reporting groups
Overall Number of Baseline Participants		472	475	947
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	472 participants	475 participants	947 participants
		60.4 (9.7)	60.9 (9.5)	60.6 (9.6)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	472 participants	475 participants	947 participants
	< 65	310 65.7%	295 62.1%	605 63.9%
	>= 65 AND < 75	134 28.4%	151 31.8%	285 30.1%
	>= 75 AND < 85	26 5.5%	28 5.9%	54 5.7%
	>= 85	2 0.4%	1 0.2%	3 0.3%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	472 participants	475 participants	947 participants
	Female	92 19.5%	78 16.4%	170 18.0%
	Male	380 80.5%	397 83.6%	777 82.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	472 participants	475 participants	947 participants
	Hispanic or Latino	40 8.5%	43 9.1%	83 8.8%
	Not Hispanic or Latino	199 42.2%	207 43.6%	406 42.9%
	Unknown or Not Reported	233 49.4%	225 47.4%	458 48.4%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	472 participants	475 participants	947 participants
	American Indian or Alaska Native	7 1.5%	5 1.1%	12 1.3%
	Asian	58 12.3%	55 11.6%	113 11.9%
	Native Hawaiian or Other Pacific Islander	1 0.2%	0 0.0%	1 0.1%
	Black or African American	15 3.2%	7 1.5%	22 2.3%
	White	379 80.3%	401 84.4%	780 82.4%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	12 2.5%	7 1.5%	19 2.0%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) in Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥20
Description	Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)
Time Frame	From randomization to date of death or date the participant was last known to be alive (Up to approximately 55 months)

Outcome Measure Data

Analysis Population Description

All randomized PD-L1 CPS >= 20 participants

Arm/Group Title	Nivolumab + Ipilimumab	EXTREME Regimen
Arm/Group Description:	Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.	Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.
Overall Number of Participants Analyzed	185	178
Median (95% Confidence Interval); Unit of Measure: Months
	17.58; (13.77 to 21.98)	14.59; (12.32 to 15.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, EXTREME Regimen
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0469
	Comments	[Not Specified]
	Method	Log Rank
	Comments	stratified regular log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 97.51%; 0.59 to 1.03
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Overall Survival (OS) in All Randomized Participants
Description	Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)
Time Frame	From randomization to date of death or date the participant was last known to be alive (Up to approximately 55 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab + Ipilimumab	EXTREME Regimen
Arm/Group Description:	Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.	Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.
Overall Number of Participants Analyzed	472	475
Median (95% Confidence Interval); Unit of Measure: Months
	13.90; (12.12 to 15.77)	13.50; (12.55 to 15.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, EXTREME Regimen
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4951
	Comments	[Not Specified]
	Method	Log Rank
	Comments	stratified regular log-rank test
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 97.9%; 0.80 to 1.13
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Overall Survival (OS) in Randomized Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥ 1
Description	Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)
Time Frame	From randomization to date of death or date the participant was last known to be alive (Up to approximately 55 months)

Outcome Measure Data

Analysis Population Description

All randomized PD-L1 CPS ≥ 1 participants

Arm/Group Title	Nivolumab + Ipilimumab	EXTREME Regimen
Arm/Group Description:	Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.	Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.
Overall Number of Participants Analyzed	355	372
Median (95% Confidence Interval); Unit of Measure: Months
	15.67; (13.70 to 18.79)	13.24; (11.07 to 14.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, EXTREME Regimen
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.69 to 0.97
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	The time from randomization to disease progression, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, or, if there is no documented progression, death based on the Blinded Independent Central Review (BICR) assessment. Participants who neither progress nor die will be censored on the date of their last tumor assessment. Participants who receive subsequent anti-cancer therapy prior to documented progression, will be censored on the date of their last tumor assessment prior to subsequent therapy. (Based on Kaplan-Meier Estimates) Progression is defined as at least a 20% increase in the sum of diameters of target lesions, in addition the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time Frame	From randomization to disease progression or death (Up to approximately 55 months)

Outcome Measure Data

Analysis Population Description

All randomized participants and randomized PD-L1 CPS >= 20 participants

Arm/Group Title		Nivolumab + Ipilimumab	EXTREME Regimen
Arm/Group Description:		Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.	Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.
Overall Number of Participants Analyzed		472	475
Median (95% Confidence Interval); Unit of Measure: Months
Randomized participants	Number Analyzed	472 participants	475 participants
		3.29; (2.83 to 4.17)	6.74; (5.78 to 7.00)
Randomized PD-L1 CPS >= 20 participants	Number Analyzed	185 participants	178 participants
		5.39; (3.09 to 6.93)	7.00; (5.62 to 8.67)

5. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	Objective Response Rate (ORR) is defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR), divided by the number randomized in the population. Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria by blinded independent central review (BICR) assessment. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	From randomization up to approximately 55 months

Outcome Measure Data

Analysis Population Description

All randomized participants and randomized PD-L1 CPS >= 20 participants

Arm/Group Title		Nivolumab + Ipilimumab	EXTREME Regimen
Arm/Group Description:		Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.	Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.
Overall Number of Participants Analyzed		472	475
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percent
All randomized participants	Number Analyzed	472 participants	475 participants
		24.2; (20.4 to 28.3)	36.8; (32.5 to 41.4)
Randomized PD-L1 CPS >= 20 participants	Number Analyzed	185 participants	178 participants
		34.1; (27.3 to 41.4)	36.0; (28.9 to 43.5)

6. Secondary Outcome

Title	Duration of Objective Response (DOR)
Description	The time between the first documented response (Complete response (CR) or partial response (PR)) and progression or death, per RECIST 1.1 by blinded independent central review (BICR) assessment. (Based on Kaplan-Meier Estimates) Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	From randomization up to approximately 55 months

Outcome Measure Data

Analysis Population Description

All randomized participants and randomized PD-L1 CPS >= 20 participants with a BOR response of CR or PR

Arm/Group Title		Nivolumab + Ipilimumab	EXTREME Regimen
Arm/Group Description:		Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.	Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.
Overall Number of Participants Analyzed		114	175
Median (95% Confidence Interval); Unit of Measure: Months
All randomized participants	Number Analyzed	114 participants	175 participants
		16.59; (9.69 to 29.40)	5.88; (5.45 to 6.97)
Randomized PD-L1 CPS >= 20 participants	Number Analyzed	63 participants	64 participants
		32.59 [1]; (12.12 to NA)	6.97; (5.65 to 10.12)

[1]

Insufficient number of participants with events

Adverse Events

Time Frame	Adverse events reported between first dose and 100 days after last dose of study therapy. (Up to approximately 55 months)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Nivolumab + Ipilimumab	EXTREME Regimen
Arm/Group Description	Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment.	Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator.
All-Cause Mortality
	Nivolumab + Ipilimumab	EXTREME Regimen
	Affected / at Risk (%)	Affected / at Risk (%)
Total	366/468 (78.21%)	363/441 (82.31%)
Serious Adverse Events
	Nivolumab + Ipilimumab	EXTREME Regimen
	Affected / at Risk (%)	Affected / at Risk (%)
Total	313/468 (66.88%)	289/441 (65.53%)
Blood and lymphatic system disorders
Anaemia † 1	1/468 (0.21%)	18/441 (4.08%)
Bone marrow failure † 1	1/468 (0.21%)	1/441 (0.23%)
Cytopenia † 1	1/468 (0.21%)	0/441 (0.00%)
Disseminated intravascular coagulation † 1	1/468 (0.21%)	0/441 (0.00%)
Febrile bone marrow aplasia † 1	0/468 (0.00%)	1/441 (0.23%)
Febrile neutropenia † 1	5/468 (1.07%)	24/441 (5.44%)
Leukopenia † 1	0/468 (0.00%)	1/441 (0.23%)
Lymphadenopathy mediastinal † 1	0/468 (0.00%)	1/441 (0.23%)
Myelosuppression † 1	0/468 (0.00%)	2/441 (0.45%)
Neutropenia † 1	0/468 (0.00%)	2/441 (0.45%)
Pancytopenia † 1	1/468 (0.21%)	3/441 (0.68%)
Thrombocytopenia † 1	0/468 (0.00%)	3/441 (0.68%)
Cardiac disorders
Acute coronary syndrome † 1	0/468 (0.00%)	1/441 (0.23%)
Acute myocardial infarction † 1	0/468 (0.00%)	2/441 (0.45%)
Angina pectoris † 1	0/468 (0.00%)	1/441 (0.23%)
Arrhythmia † 1	1/468 (0.21%)	0/441 (0.00%)
Atrial fibrillation † 1	1/468 (0.21%)	2/441 (0.45%)
Atrial flutter † 1	0/468 (0.00%)	1/441 (0.23%)
Cardiac arrest † 1	4/468 (0.85%)	1/441 (0.23%)
Cardiac tamponade † 1	0/468 (0.00%)	1/441 (0.23%)
Cardio-respiratory arrest † 1	1/468 (0.21%)	0/441 (0.00%)
Cardiogenic shock † 1	0/468 (0.00%)	1/441 (0.23%)
Immune-mediated myocarditis † 1	1/468 (0.21%)	0/441 (0.00%)
Myocardial infarction † 1	0/468 (0.00%)	1/441 (0.23%)
Myocardial ischaemia † 1	0/468 (0.00%)	1/441 (0.23%)
Palpitations † 1	1/468 (0.21%)	0/441 (0.00%)
Pericardial effusion † 1	1/468 (0.21%)	1/441 (0.23%)
Pericarditis † 1	1/468 (0.21%)	0/441 (0.00%)
Tachycardia † 1	0/468 (0.00%)	1/441 (0.23%)
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula † 1	0/468 (0.00%)	2/441 (0.45%)
Endocrine disorders
Adrenal insufficiency † 1	4/468 (0.85%)	0/441 (0.00%)
Adrenocorticotropic hormone deficiency † 1	1/468 (0.21%)	0/441 (0.00%)
Autoimmune thyroiditis † 1	1/468 (0.21%)	0/441 (0.00%)
Hyperthyroidism † 1	1/468 (0.21%)	0/441 (0.00%)
Hypophysitis † 1	2/468 (0.43%)	0/441 (0.00%)
Hypopituitarism † 1	1/468 (0.21%)	0/441 (0.00%)
Hypothyroidism † 1	1/468 (0.21%)	0/441 (0.00%)
Immune-mediated hypophysitis † 1	1/468 (0.21%)	0/441 (0.00%)
Inappropriate antidiuretic hormone secretion † 1	0/468 (0.00%)	1/441 (0.23%)
Lymphocytic hypophysitis † 1	1/468 (0.21%)	0/441 (0.00%)
Secondary adrenocortical insufficiency † 1	1/468 (0.21%)	0/441 (0.00%)
Eye disorders
Corneal perforation † 1	1/468 (0.21%)	0/441 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	1/468 (0.21%)	1/441 (0.23%)
Abdominal pain upper † 1	0/468 (0.00%)	1/441 (0.23%)
Alcoholic pancreatitis † 1	1/468 (0.21%)	0/441 (0.00%)
Autoimmune colitis † 1	1/468 (0.21%)	0/441 (0.00%)
Colitis † 1	10/468 (2.14%)	2/441 (0.45%)
Constipation † 1	2/468 (0.43%)	3/441 (0.68%)
Cyclic vomiting syndrome † 1	0/468 (0.00%)	2/441 (0.45%)
Diarrhoea † 1	9/468 (1.92%)	8/441 (1.81%)
Duodenal perforation † 1	0/468 (0.00%)	1/441 (0.23%)
Duodenal ulcer † 1	0/468 (0.00%)	1/441 (0.23%)
Dyspepsia † 1	0/468 (0.00%)	1/441 (0.23%)
Dysphagia † 1	8/468 (1.71%)	10/441 (2.27%)
Gastric ulcer † 1	1/468 (0.21%)	0/441 (0.00%)
Gastritis erosive † 1	0/468 (0.00%)	1/441 (0.23%)
Gastrointestinal haemorrhage † 1	0/468 (0.00%)	1/441 (0.23%)
Haematemesis † 1	0/468 (0.00%)	2/441 (0.45%)
Immune-mediated enterocolitis † 1	1/468 (0.21%)	0/441 (0.00%)
Intestinal obstruction † 1	3/468 (0.64%)	1/441 (0.23%)
Intestinal perforation † 1	0/468 (0.00%)	2/441 (0.45%)
Lower gastrointestinal haemorrhage † 1	0/468 (0.00%)	1/441 (0.23%)
Mechanical ileus † 1	0/468 (0.00%)	1/441 (0.23%)
Melaena † 1	0/468 (0.00%)	1/441 (0.23%)
Mesenteric haematoma † 1	0/468 (0.00%)	1/441 (0.23%)
Mouth haemorrhage † 1	3/468 (0.64%)	3/441 (0.68%)
Nausea † 1	1/468 (0.21%)	4/441 (0.91%)
Oesophageal stenosis † 1	2/468 (0.43%)	0/441 (0.00%)
Oral cavity fistula † 1	2/468 (0.43%)	1/441 (0.23%)
Pancreatic failure † 1	1/468 (0.21%)	0/441 (0.00%)
Pancreatic pseudocyst † 1	1/468 (0.21%)	0/441 (0.00%)
Pancreatitis † 1	0/468 (0.00%)	1/441 (0.23%)
Rectal haemorrhage † 1	1/468 (0.21%)	0/441 (0.00%)
Stomatitis † 1	0/468 (0.00%)	6/441 (1.36%)
Subileus † 1	0/468 (0.00%)	1/441 (0.23%)
Swollen tongue † 1	1/468 (0.21%)	0/441 (0.00%)
Upper gastrointestinal haemorrhage † 1	3/468 (0.64%)	0/441 (0.00%)
Vomiting † 1	4/468 (0.85%)	4/441 (0.91%)
General disorders
Asthenia † 1	1/468 (0.21%)	3/441 (0.68%)
Chest pain † 1	1/468 (0.21%)	0/441 (0.00%)
Complication associated with device † 1	1/468 (0.21%)	1/441 (0.23%)
Death † 1	1/468 (0.21%)	1/441 (0.23%)
Disease progression † 1	0/468 (0.00%)	1/441 (0.23%)
Face oedema † 1	1/468 (0.21%)	1/441 (0.23%)
Fatigue † 1	1/468 (0.21%)	1/441 (0.23%)
General physical health deterioration † 1	4/468 (0.85%)	6/441 (1.36%)
Inflammation † 1	0/468 (0.00%)	1/441 (0.23%)
Influenza like illness † 1	2/468 (0.43%)	0/441 (0.00%)
Lithiasis † 1	0/468 (0.00%)	1/441 (0.23%)
Localised oedema † 1	1/468 (0.21%)	0/441 (0.00%)
Mucosal haemorrhage † 1	0/468 (0.00%)	1/441 (0.23%)
Mucosal inflammation † 1	0/468 (0.00%)	7/441 (1.59%)
Multiple organ dysfunction syndrome † 1	0/468 (0.00%)	1/441 (0.23%)
Non-cardiac chest pain † 1	2/468 (0.43%)	2/441 (0.45%)
Pain † 1	3/468 (0.64%)	2/441 (0.45%)
Performance status decreased † 1	1/468 (0.21%)	0/441 (0.00%)
Pneumatosis † 1	0/468 (0.00%)	1/441 (0.23%)
Pyrexia † 1	4/468 (0.85%)	9/441 (2.04%)
Stenosis † 1	1/468 (0.21%)	0/441 (0.00%)
Sudden cardiac death † 1	1/468 (0.21%)	0/441 (0.00%)
Sudden death † 1	7/468 (1.50%)	7/441 (1.59%)
Suprapubic pain † 1	1/468 (0.21%)	0/441 (0.00%)
Swelling face † 1	1/468 (0.21%)	0/441 (0.00%)
Ulcer haemorrhage † 1	0/468 (0.00%)	1/441 (0.23%)
Hepatobiliary disorders
Autoimmune hepatitis † 1	4/468 (0.85%)	0/441 (0.00%)
Cholecystitis † 1	3/468 (0.64%)	1/441 (0.23%)
Cholecystocholangitis † 1	1/468 (0.21%)	0/441 (0.00%)
Hepatic cytolysis † 1	1/468 (0.21%)	0/441 (0.00%)
Hepatic failure † 1	1/468 (0.21%)	1/441 (0.23%)
Hepatic function abnormal † 1	2/468 (0.43%)	0/441 (0.00%)
Hepatitis † 1	3/468 (0.64%)	1/441 (0.23%)
Hepatitis acute † 1	0/468 (0.00%)	1/441 (0.23%)
Immune-mediated hepatitis † 1	2/468 (0.43%)	0/441 (0.00%)
Immune system disorders
Anaphylactic shock † 1	0/468 (0.00%)	1/441 (0.23%)
Hypersensitivity † 1	0/468 (0.00%)	1/441 (0.23%)
Infections and infestations
Abscess limb † 1	0/468 (0.00%)	1/441 (0.23%)
Abscess neck † 1	1/468 (0.21%)	0/441 (0.00%)
Actinomycosis † 1	1/468 (0.21%)	0/441 (0.00%)
Anal abscess † 1	0/468 (0.00%)	1/441 (0.23%)
Arthritis infective † 1	0/468 (0.00%)	1/441 (0.23%)
Bacteraemia † 1	1/468 (0.21%)	3/441 (0.68%)
Bacterial infection † 1	0/468 (0.00%)	1/441 (0.23%)
Bacterial sepsis † 1	1/468 (0.21%)	0/441 (0.00%)
Bronchitis † 1	2/468 (0.43%)	2/441 (0.45%)
Candida infection † 1	0/468 (0.00%)	1/441 (0.23%)
Catheter site cellulitis † 1	0/468 (0.00%)	1/441 (0.23%)
Catheter site infection † 1	0/468 (0.00%)	1/441 (0.23%)
Cellulitis † 1	5/468 (1.07%)	2/441 (0.45%)
Clostridium difficile colitis † 1	0/468 (0.00%)	1/441 (0.23%)
Cystitis † 1	1/468 (0.21%)	0/441 (0.00%)
Device related infection † 1	1/468 (0.21%)	3/441 (0.68%)
Device related sepsis † 1	2/468 (0.43%)	0/441 (0.00%)
Diverticulitis † 1	1/468 (0.21%)	1/441 (0.23%)
Emphysematous cystitis † 1	0/468 (0.00%)	1/441 (0.23%)
Enterobacter sepsis † 1	1/468 (0.21%)	0/441 (0.00%)
Epiglottitis † 1	2/468 (0.43%)	0/441 (0.00%)
Erysipelas † 1	2/468 (0.43%)	0/441 (0.00%)
Febrile infection † 1	1/468 (0.21%)	0/441 (0.00%)
Fungal infection † 1	1/468 (0.21%)	0/441 (0.00%)
Gastroenteritis † 1	2/468 (0.43%)	0/441 (0.00%)
Gastrointestinal infection † 1	0/468 (0.00%)	1/441 (0.23%)
Herpes zoster † 1	0/468 (0.00%)	1/441 (0.23%)
Herpes zoster oticus † 1	1/468 (0.21%)	0/441 (0.00%)
Impetigo † 1	1/468 (0.21%)	0/441 (0.00%)
Infected fistula † 1	1/468 (0.21%)	1/441 (0.23%)
Infection † 1	3/468 (0.64%)	2/441 (0.45%)
Infective exacerbation of chronic obstructive airways disease † 1	0/468 (0.00%)	1/441 (0.23%)
Infective spondylitis † 1	0/468 (0.00%)	1/441 (0.23%)
Influenza † 1	1/468 (0.21%)	0/441 (0.00%)
Laryngitis † 1	1/468 (0.21%)	0/441 (0.00%)
Localised infection † 1	0/468 (0.00%)	1/441 (0.23%)
Lower respiratory tract infection † 1	1/468 (0.21%)	1/441 (0.23%)
Lung abscess † 1	0/468 (0.00%)	1/441 (0.23%)
Mediastinitis † 1	0/468 (0.00%)	1/441 (0.23%)
Meningitis † 1	1/468 (0.21%)	0/441 (0.00%)
Mucosal infection † 1	1/468 (0.21%)	0/441 (0.00%)
Neutropenic infection † 1	0/468 (0.00%)	1/441 (0.23%)
Neutropenic sepsis † 1	3/468 (0.64%)	1/441 (0.23%)
Oral infection † 1	0/468 (0.00%)	1/441 (0.23%)
Otitis externa † 1	0/468 (0.00%)	1/441 (0.23%)
Parametritis † 1	0/468 (0.00%)	1/441 (0.23%)
Paronychia † 1	0/468 (0.00%)	1/441 (0.23%)
Periorbital cellulitis † 1	1/468 (0.21%)	0/441 (0.00%)
Pneumocystis jirovecii pneumonia † 1	1/468 (0.21%)	0/441 (0.00%)
Pneumonia † 1	24/468 (5.13%)	31/441 (7.03%)
Pneumonia bacterial † 1	2/468 (0.43%)	0/441 (0.00%)
Pneumonia cytomegaloviral † 1	1/468 (0.21%)	0/441 (0.00%)
Pneumonia klebsiella † 1	0/468 (0.00%)	1/441 (0.23%)
Pneumonia necrotising † 1	0/468 (0.00%)	1/441 (0.23%)
Pneumonia pseudomonal † 1	1/468 (0.21%)	1/441 (0.23%)
Pseudomonas infection † 1	1/468 (0.21%)	1/441 (0.23%)
Pulmonary sepsis † 1	1/468 (0.21%)	0/441 (0.00%)
Respiratory tract infection † 1	3/468 (0.64%)	3/441 (0.68%)
Sepsis † 1	10/468 (2.14%)	10/441 (2.27%)
Septic shock † 1	3/468 (0.64%)	3/441 (0.68%)
Sialoadenitis † 1	0/468 (0.00%)	1/441 (0.23%)
Sinusitis † 1	1/468 (0.21%)	0/441 (0.00%)
Skin infection † 1	0/468 (0.00%)	1/441 (0.23%)
Soft tissue infection † 1	1/468 (0.21%)	3/441 (0.68%)
Staphylococcal bacteraemia † 1	0/468 (0.00%)	2/441 (0.45%)
Staphylococcal infection † 1	1/468 (0.21%)	0/441 (0.00%)
Staphylococcal sepsis † 1	0/468 (0.00%)	1/441 (0.23%)
Stoma site infection † 1	0/468 (0.00%)	2/441 (0.45%)
Streptococcal bacteraemia † 1	1/468 (0.21%)	0/441 (0.00%)
Subcutaneous abscess † 1	1/468 (0.21%)	0/441 (0.00%)
Tuberculosis † 1	1/468 (0.21%)	0/441 (0.00%)
Upper respiratory tract infection † 1	3/468 (0.64%)	0/441 (0.00%)
Urinary tract infection † 1	2/468 (0.43%)	0/441 (0.00%)
Vascular access site infection † 1	0/468 (0.00%)	1/441 (0.23%)
Vascular device infection † 1	0/468 (0.00%)	2/441 (0.45%)
Injury, poisoning and procedural complications
Accidental overdose † 1	1/468 (0.21%)	0/441 (0.00%)
Device placement issue † 1	0/468 (0.00%)	1/441 (0.23%)
Facial bones fracture † 1	0/468 (0.00%)	1/441 (0.23%)
Fall † 1	0/468 (0.00%)	2/441 (0.45%)
Humerus fracture † 1	0/468 (0.00%)	1/441 (0.23%)
Infusion related reaction † 1	2/468 (0.43%)	1/441 (0.23%)
Post procedural complication † 1	0/468 (0.00%)	1/441 (0.23%)
Post procedural haemorrhage † 1	0/468 (0.00%)	2/441 (0.45%)
Radiation injury † 1	0/468 (0.00%)	1/441 (0.23%)
Radiation necrosis † 1	0/468 (0.00%)	1/441 (0.23%)
Stoma site inflammation † 1	0/468 (0.00%)	1/441 (0.23%)
Stoma site ulcer † 1	0/468 (0.00%)	1/441 (0.23%)
Tracheal haemorrhage † 1	1/468 (0.21%)	0/441 (0.00%)
Tracheal obstruction † 1	0/468 (0.00%)	1/441 (0.23%)
Tracheostomy malfunction † 1	0/468 (0.00%)	1/441 (0.23%)
Unintentional medical device removal † 1	1/468 (0.21%)	0/441 (0.00%)
Wound dehiscence † 1	1/468 (0.21%)	0/441 (0.00%)
Wound necrosis † 1	1/468 (0.21%)	0/441 (0.00%)
Investigations
Amylase increased † 1	0/468 (0.00%)	1/441 (0.23%)
Aspartate aminotransferase increased † 1	1/468 (0.21%)	0/441 (0.00%)
C-reactive protein increased † 1	1/468 (0.21%)	1/441 (0.23%)
General physical condition abnormal † 1	1/468 (0.21%)	2/441 (0.45%)
Haemoglobin decreased † 1	1/468 (0.21%)	1/441 (0.23%)
Hepatic enzyme increased † 1	1/468 (0.21%)	1/441 (0.23%)
Lipase increased † 1	1/468 (0.21%)	0/441 (0.00%)
Liver function test increased † 1	1/468 (0.21%)	0/441 (0.00%)
Neutrophil count decreased † 1	0/468 (0.00%)	3/441 (0.68%)
Platelet count decreased † 1	0/468 (0.00%)	2/441 (0.45%)
Transaminases increased † 1	2/468 (0.43%)	0/441 (0.00%)
Weight decreased † 1	1/468 (0.21%)	2/441 (0.45%)
Metabolism and nutrition disorders
Cachexia † 1	0/468 (0.00%)	1/441 (0.23%)
Decreased appetite † 1	3/468 (0.64%)	4/441 (0.91%)
Dehydration † 1	7/468 (1.50%)	4/441 (0.91%)
Diabetic ketoacidosis † 1	1/468 (0.21%)	0/441 (0.00%)
Electrolyte depletion † 1	0/468 (0.00%)	1/441 (0.23%)
Electrolyte imbalance † 1	0/468 (0.00%)	5/441 (1.13%)
Feeding disorder † 1	1/468 (0.21%)	0/441 (0.00%)
Gout † 1	1/468 (0.21%)	0/441 (0.00%)
Hyperamylasaemia † 1	1/468 (0.21%)	0/441 (0.00%)
Hypercalcaemia † 1	7/468 (1.50%)	2/441 (0.45%)
Hyperglycaemia † 1	2/468 (0.43%)	1/441 (0.23%)
Hyperlipasaemia † 1	1/468 (0.21%)	0/441 (0.00%)
Hypocalcaemia † 1	1/468 (0.21%)	1/441 (0.23%)
Hypokalaemia † 1	2/468 (0.43%)	7/441 (1.59%)
Hypomagnesaemia † 1	0/468 (0.00%)	2/441 (0.45%)
Hyponatraemia † 1	3/468 (0.64%)	4/441 (0.91%)
Hypophosphataemia † 1	0/468 (0.00%)	1/441 (0.23%)
Malnutrition † 1	3/468 (0.64%)	3/441 (0.68%)
Tumour lysis syndrome † 1	1/468 (0.21%)	0/441 (0.00%)
Type 1 diabetes mellitus † 1	1/468 (0.21%)	0/441 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/468 (0.21%)	1/441 (0.23%)
Arthritis † 1	2/468 (0.43%)	0/441 (0.00%)
Back pain † 1	2/468 (0.43%)	1/441 (0.23%)
Flank pain † 1	0/468 (0.00%)	1/441 (0.23%)
Gouty arthritis † 1	1/468 (0.21%)	0/441 (0.00%)
Haematoma muscle † 1	1/468 (0.21%)	0/441 (0.00%)
Immobilisation syndrome † 1	0/468 (0.00%)	1/441 (0.23%)
Jaw fistula † 1	1/468 (0.21%)	0/441 (0.00%)
Muscular weakness † 1	1/468 (0.21%)	0/441 (0.00%)
Musculoskeletal chest pain † 1	0/468 (0.00%)	1/441 (0.23%)
Musculoskeletal pain † 1	0/468 (0.00%)	1/441 (0.23%)
Osteonecrosis † 1	1/468 (0.21%)	0/441 (0.00%)
Pathological fracture † 1	1/468 (0.21%)	0/441 (0.00%)
Rhabdomyolysis † 1	0/468 (0.00%)	1/441 (0.23%)
Rotator cuff syndrome † 1	1/468 (0.21%)	0/441 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer † 1	0/468 (0.00%)	1/441 (0.23%)
Cancer pain † 1	2/468 (0.43%)	2/441 (0.45%)
Colorectal cancer † 1	1/468 (0.21%)	0/441 (0.00%)
Follicular lymphoma † 1	1/468 (0.21%)	0/441 (0.00%)
Infected neoplasm † 1	2/468 (0.43%)	0/441 (0.00%)
Lentigo maligna † 1	0/468 (0.00%)	1/441 (0.23%)
Malignant neoplasm progression † 1	99/468 (21.15%)	99/441 (22.45%)
Metastatic squamous cell carcinoma † 1	1/468 (0.21%)	0/441 (0.00%)
Neoplasm malignant † 1	1/468 (0.21%)	0/441 (0.00%)
Neoplasm progression † 1	4/468 (0.85%)	2/441 (0.45%)
Non-small cell lung cancer † 1	1/468 (0.21%)	0/441 (0.00%)
Oesophageal carcinoma † 1	1/468 (0.21%)	1/441 (0.23%)
Oncologic complication † 1	1/468 (0.21%)	0/441 (0.00%)
Rectal adenocarcinoma † 1	1/468 (0.21%)	0/441 (0.00%)
Skin cancer † 1	1/468 (0.21%)	0/441 (0.00%)
Small cell lung cancer † 1	1/468 (0.21%)	0/441 (0.00%)
Squamous cell carcinoma † 1	2/468 (0.43%)	1/441 (0.23%)
Tumour associated fever † 1	0/468 (0.00%)	1/441 (0.23%)
Tumour haemorrhage † 1	20/468 (4.27%)	9/441 (2.04%)
Tumour pain † 1	2/468 (0.43%)	1/441 (0.23%)
Nervous system disorders
Carotid artery stenosis † 1	0/468 (0.00%)	1/441 (0.23%)
Cerebral infarction † 1	0/468 (0.00%)	1/441 (0.23%)
Cerebrovascular accident † 1	1/468 (0.21%)	5/441 (1.13%)
Cervicobrachial syndrome † 1	1/468 (0.21%)	0/441 (0.00%)
Depressed level of consciousness † 1	1/468 (0.21%)	0/441 (0.00%)
Dizziness † 1	1/468 (0.21%)	0/441 (0.00%)
Encephalopathy † 1	0/468 (0.00%)	2/441 (0.45%)
Epilepsy † 1	1/468 (0.21%)	0/441 (0.00%)
Haemorrhage intracranial † 1	0/468 (0.00%)	1/441 (0.23%)
Hemiparesis † 1	0/468 (0.00%)	1/441 (0.23%)
Hypoaesthesia † 1	0/468 (0.00%)	1/441 (0.23%)
Hypotonia † 1	1/468 (0.21%)	0/441 (0.00%)
Ischaemic stroke † 1	0/468 (0.00%)	2/441 (0.45%)
Lumbar radiculopathy † 1	1/468 (0.21%)	0/441 (0.00%)
Metabolic encephalopathy † 1	1/468 (0.21%)	0/441 (0.00%)
Nervous system disorder † 1	1/468 (0.21%)	0/441 (0.00%)
Neuropathy peripheral † 1	1/468 (0.21%)	0/441 (0.00%)
Paraparesis † 1	1/468 (0.21%)	0/441 (0.00%)
Peripheral motor neuropathy † 1	1/468 (0.21%)	0/441 (0.00%)
Seizure † 1	2/468 (0.43%)	0/441 (0.00%)
Subarachnoid haemorrhage † 1	1/468 (0.21%)	0/441 (0.00%)
Syncope † 1	2/468 (0.43%)	3/441 (0.68%)
Vocal cord paralysis † 1	1/468 (0.21%)	0/441 (0.00%)
Product Issues
Device dislocation † 1	2/468 (0.43%)	2/441 (0.45%)
Device occlusion † 1	0/468 (0.00%)	2/441 (0.45%)
Psychiatric disorders
Anxiety † 1	1/468 (0.21%)	0/441 (0.00%)
Completed suicide † 1	0/468 (0.00%)	1/441 (0.23%)
Delirium tremens † 1	0/468 (0.00%)	1/441 (0.23%)
Disorientation † 1	1/468 (0.21%)	0/441 (0.00%)
Eating disorder † 1	1/468 (0.21%)	0/441 (0.00%)
Hallucination † 1	0/468 (0.00%)	1/441 (0.23%)
Mania † 1	0/468 (0.00%)	1/441 (0.23%)
Suicide attempt † 1	1/468 (0.21%)	0/441 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	0/468 (0.00%)	7/441 (1.59%)
Anuria † 1	0/468 (0.00%)	1/441 (0.23%)
Cystitis noninfective † 1	0/468 (0.00%)	1/441 (0.23%)
Nephritis † 1	1/468 (0.21%)	0/441 (0.00%)
Nephropathy † 1	1/468 (0.21%)	0/441 (0.00%)
Renal failure † 1	0/468 (0.00%)	3/441 (0.68%)
Ureterolithiasis † 1	1/468 (0.21%)	0/441 (0.00%)
Urinary bladder polyp † 1	1/468 (0.21%)	0/441 (0.00%)
Reproductive system and breast disorders
Cervix haemorrhage uterine † 1	1/468 (0.21%)	0/441 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema † 1	1/468 (0.21%)	0/441 (0.00%)
Acute respiratory distress syndrome † 1	0/468 (0.00%)	1/441 (0.23%)
Acute respiratory failure † 1	2/468 (0.43%)	0/441 (0.00%)
Asphyxia † 1	1/468 (0.21%)	0/441 (0.00%)
Aspiration † 1	1/468 (0.21%)	1/441 (0.23%)
Atelectasis † 1	1/468 (0.21%)	0/441 (0.00%)
Bronchial obstruction † 1	2/468 (0.43%)	0/441 (0.00%)
Bronchopneumopathy † 1	0/468 (0.00%)	1/441 (0.23%)
Chronic obstructive pulmonary disease † 1	0/468 (0.00%)	1/441 (0.23%)
Dyspnoea † 1	15/468 (3.21%)	4/441 (0.91%)
Haemoptysis † 1	1/468 (0.21%)	2/441 (0.45%)
Hypoxia † 1	1/468 (0.21%)	0/441 (0.00%)
Interstitial lung disease † 1	2/468 (0.43%)	0/441 (0.00%)
Laryngeal dyspnoea † 1	1/468 (0.21%)	0/441 (0.00%)
Laryngeal obstruction † 1	1/468 (0.21%)	0/441 (0.00%)
Laryngeal oedema † 1	1/468 (0.21%)	0/441 (0.00%)
Laryngeal stenosis † 1	1/468 (0.21%)	0/441 (0.00%)
Lower respiratory tract congestion † 1	0/468 (0.00%)	1/441 (0.23%)
Lung disorder † 1	0/468 (0.00%)	3/441 (0.68%)
Obstructive airways disorder † 1	2/468 (0.43%)	2/441 (0.45%)
Oropharyngeal pain † 1	0/468 (0.00%)	1/441 (0.23%)
Pharyngeal haemorrhage † 1	1/468 (0.21%)	2/441 (0.45%)
Pleural effusion † 1	7/468 (1.50%)	3/441 (0.68%)
Pneumomediastinum † 1	0/468 (0.00%)	1/441 (0.23%)
Pneumonia aspiration † 1	8/468 (1.71%)	7/441 (1.59%)
Pneumonitis † 1	8/468 (1.71%)	0/441 (0.00%)
Pneumothorax † 1	1/468 (0.21%)	1/441 (0.23%)
Pulmonary embolism † 1	7/468 (1.50%)	7/441 (1.59%)
Pulmonary mass † 1	0/468 (0.00%)	1/441 (0.23%)
Respiratory arrest † 1	1/468 (0.21%)	0/441 (0.00%)
Respiratory disorder † 1	0/468 (0.00%)	1/441 (0.23%)
Respiratory distress † 1	1/468 (0.21%)	1/441 (0.23%)
Respiratory failure † 1	2/468 (0.43%)	3/441 (0.68%)
Sleep apnoea syndrome † 1	1/468 (0.21%)	0/441 (0.00%)
Tracheal fistula † 1	0/468 (0.00%)	1/441 (0.23%)
Tracheal stenosis † 1	1/468 (0.21%)	1/441 (0.23%)
Skin and subcutaneous tissue disorders
Pemphigoid † 1	1/468 (0.21%)	0/441 (0.00%)
Pemphigus † 1	1/468 (0.21%)	0/441 (0.00%)
Pruritus † 1	1/468 (0.21%)	0/441 (0.00%)
Psoriasis † 1	1/468 (0.21%)	1/441 (0.23%)
Rash † 1	1/468 (0.21%)	0/441 (0.00%)
Rash erythematous † 1	0/468 (0.00%)	1/441 (0.23%)
Rash maculo-papular † 1	1/468 (0.21%)	0/441 (0.00%)
Subcutaneous emphysema † 1	1/468 (0.21%)	0/441 (0.00%)
Vascular disorders
Aortic aneurysm rupture † 1	1/468 (0.21%)	0/441 (0.00%)
Arterial haemorrhage † 1	0/468 (0.00%)	1/441 (0.23%)
Circulatory collapse † 1	0/468 (0.00%)	2/441 (0.45%)
Deep vein thrombosis † 1	0/468 (0.00%)	3/441 (0.68%)
Embolism † 1	1/468 (0.21%)	2/441 (0.45%)
Haemorrhage † 1	4/468 (0.85%)	1/441 (0.23%)
Hypertension † 1	1/468 (0.21%)	0/441 (0.00%)
Hypotension † 1	2/468 (0.43%)	3/441 (0.68%)
Hypovolaemic shock † 1	1/468 (0.21%)	0/441 (0.00%)
Internal haemorrhage † 1	0/468 (0.00%)	1/441 (0.23%)
Lymphoedema † 1	1/468 (0.21%)	0/441 (0.00%)
Orthostatic hypotension † 1	1/468 (0.21%)	1/441 (0.23%)
Peripheral artery occlusion † 1	0/468 (0.00%)	1/441 (0.23%)
Peripheral ischaemia † 1	1/468 (0.21%)	0/441 (0.00%)
Shock haemorrhagic † 1	0/468 (0.00%)	1/441 (0.23%)
Thrombosis † 1	0/468 (0.00%)	2/441 (0.45%)
Vascular rupture † 1	1/468 (0.21%)	0/441 (0.00%)
1 Term from vocabulary, 24.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Nivolumab + Ipilimumab	EXTREME Regimen
	Affected / at Risk (%)	Affected / at Risk (%)
Total	420/468 (89.74%)	429/441 (97.28%)
Blood and lymphatic system disorders
Anaemia † 1	101/468 (21.58%)	190/441 (43.08%)
Leukopenia † 1	6/468 (1.28%)	35/441 (7.94%)
Lymphopenia † 1	17/468 (3.63%)	25/441 (5.67%)
Neutropenia † 1	11/468 (2.35%)	131/441 (29.71%)
Thrombocytopenia † 1	7/468 (1.50%)	109/441 (24.72%)
Ear and labyrinth disorders
Tinnitus † 1	4/468 (0.85%)	27/441 (6.12%)
Endocrine disorders
Hyperthyroidism † 1	40/468 (8.55%)	2/441 (0.45%)
Hypothyroidism † 1	84/468 (17.95%)	19/441 (4.31%)
Gastrointestinal disorders
Abdominal pain † 1	35/468 (7.48%)	36/441 (8.16%)
Constipation † 1	95/468 (20.30%)	157/441 (35.60%)
Diarrhoea † 1	103/468 (22.01%)	141/441 (31.97%)
Dyspepsia † 1	12/468 (2.56%)	29/441 (6.58%)
Dysphagia † 1	52/468 (11.11%)	49/441 (11.11%)
Nausea † 1	101/468 (21.58%)	227/441 (51.47%)
Stomatitis † 1	24/468 (5.13%)	104/441 (23.58%)
Vomiting † 1	57/468 (12.18%)	121/441 (27.44%)
General disorders
Asthenia † 1	72/468 (15.38%)	106/441 (24.04%)
Fatigue † 1	123/468 (26.28%)	153/441 (34.69%)
Mucosal inflammation † 1	27/468 (5.77%)	136/441 (30.84%)
Oedema peripheral † 1	30/468 (6.41%)	29/441 (6.58%)
Pain † 1	26/468 (5.56%)	16/441 (3.63%)
Pyrexia † 1	49/468 (10.47%)	45/441 (10.20%)
Infections and infestations
Folliculitis † 1	6/468 (1.28%)	33/441 (7.48%)
Oral candidiasis † 1	19/468 (4.06%)	29/441 (6.58%)
Paronychia † 1	9/468 (1.92%)	95/441 (21.54%)
Pneumonia † 1	40/468 (8.55%)	24/441 (5.44%)
Upper respiratory tract infection † 1	26/468 (5.56%)	19/441 (4.31%)
Investigations
Alanine aminotransferase increased † 1	35/468 (7.48%)	23/441 (5.22%)
Amylase increased † 1	32/468 (6.84%)	17/441 (3.85%)
Aspartate aminotransferase increased † 1	38/468 (8.12%)	18/441 (4.08%)
Blood alkaline phosphatase increased † 1	27/468 (5.77%)	19/441 (4.31%)
Blood creatinine increased † 1	17/468 (3.63%)	34/441 (7.71%)
Lipase increased † 1	50/468 (10.68%)	18/441 (4.08%)
Neutrophil count decreased † 1	19/468 (4.06%)	66/441 (14.97%)
Platelet count decreased † 1	7/468 (1.50%)	60/441 (13.61%)
Weight decreased † 1	57/468 (12.18%)	81/441 (18.37%)
White blood cell count decreased † 1	12/468 (2.56%)	36/441 (8.16%)
Metabolism and nutrition disorders
Decreased appetite † 1	73/468 (15.60%)	115/441 (26.08%)
Dehydration † 1	6/468 (1.28%)	26/441 (5.90%)
Hypercalcaemia † 1	31/468 (6.62%)	14/441 (3.17%)
Hyperglycaemia † 1	24/468 (5.13%)	20/441 (4.54%)
Hypoalbuminaemia † 1	33/468 (7.05%)	26/441 (5.90%)
Hypocalcaemia † 1	13/468 (2.78%)	45/441 (10.20%)
Hypokalaemia † 1	28/468 (5.98%)	93/441 (21.09%)
Hypomagnesaemia † 1	34/468 (7.26%)	146/441 (33.11%)
Hyponatraemia † 1	39/468 (8.33%)	35/441 (7.94%)
Hypophosphataemia † 1	10/468 (2.14%)	34/441 (7.71%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	59/468 (12.61%)	21/441 (4.76%)
Back pain † 1	27/468 (5.77%)	20/441 (4.54%)
Neck pain † 1	38/468 (8.12%)	37/441 (8.39%)
Nervous system disorders
Dizziness † 1	20/468 (4.27%)	31/441 (7.03%)
Headache † 1	30/468 (6.41%)	30/441 (6.80%)
Neuropathy peripheral † 1	10/468 (2.14%)	34/441 (7.71%)
Psychiatric disorders
Insomnia † 1	35/468 (7.48%)	37/441 (8.39%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	63/468 (13.46%)	34/441 (7.71%)
Dyspnoea † 1	59/468 (12.61%)	52/441 (11.79%)
Epistaxis † 1	5/468 (1.07%)	31/441 (7.03%)
Skin and subcutaneous tissue disorders
Alopecia † 1	6/468 (1.28%)	40/441 (9.07%)
Dermatitis acneiform † 1	23/468 (4.91%)	147/441 (33.33%)
Dry skin † 1	35/468 (7.48%)	79/441 (17.91%)
Pruritus † 1	88/468 (18.80%)	38/441 (8.62%)
Rash † 1	90/468 (19.23%)	178/441 (40.36%)
Skin fissures † 1	4/468 (0.85%)	65/441 (14.74%)
Vascular disorders
Hypotension † 1	14/468 (2.99%)	25/441 (5.67%)
1 Term from vocabulary, 24.0; † 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.Trials@bms.com

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

Hwang M, Seiwert TY. Are taxanes the future for head and neck cancer? Pragmatism in the immunotherapy era. Lancet Oncol. 2021 Apr;22(4):413-415. doi: 10.1016/S1470-2045(21)00121-2. Epub 2021 Mar 5. No abstract available. Erratum In: Lancet Oncol. 2021 Apr;22(4):e134.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02741570
• Other Study ID Numbers: CA209-651; 2016-000725-39 ( EudraCT Number )
• First Submitted: April 13, 2016
• First Posted: April 18, 2016
• Results First Submitted: April 6, 2022
• Results First Posted: May 3, 2022
• Last Update Posted: October 20, 2022