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Trial record 1 of 1 for:    CA209-651
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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02741570
Recruitment Status : Active, not recruiting
First Posted : April 18, 2016
Results First Posted : May 3, 2022
Last Update Posted : May 3, 2022
Sponsor:
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
Recruitment Details  
Pre-assignment Details 947 participants randomized to receive study treatment. 909 participants received study treatment.
Arm/Group Title Nivolumab + Ipilimumab EXTREME Regimen
Hide 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
Arm/Group Title Nivolumab + Ipilimumab EXTREME Regimen Total
Hide 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
Hide 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%
1.Primary Outcome
Title Overall Survival (OS) in Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥20
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized PD-L1 CPS >= 20 participants
Arm/Group Title Nivolumab + Ipilimumab EXTREME Regimen
Hide 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)
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Nivolumab + Ipilimumab EXTREME Regimen
Hide 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)
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized PD-L1 CPS ≥ 1 participants
Arm/Group Title Nivolumab + Ipilimumab EXTREME Regimen
Hide 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)
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants and randomized PD-L1 CPS >= 20 participants
Arm/Group Title Nivolumab + Ipilimumab EXTREME Regimen
Hide 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)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants and randomized PD-L1 CPS >= 20 participants
Arm/Group Title Nivolumab + Ipilimumab EXTREME Regimen
Hide 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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
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
Hide 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%) 
Hide 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
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Hide 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
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
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Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
Phone: Please email
EMail: Clinical.Trials@bms.com
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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: May 3, 2022