An Open-Label, Randomized, Phase 3 Trial of Nivolumab Versus Investigator's Choice Chemotherapy as First-Line Therapy for Stage IV or Recurrent PD-L1+ Non-Small Cell Lung Cancer (CheckMate 026)

• ClinicalTrials.gov Identifier: NCT02041533
• Recruitment Status: Completed
• First Posted: January 22, 2014
• Results First Posted: July 26, 2017
• Last Update Posted: March 2, 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: Stage IV or Recurrent Non-Small Cell Lung Cancer
• Interventions: Biological: Nivolumab; Drug: Gemcitabine; Drug: Cisplatin; Drug: Carboplatin; Drug: Paclitaxel; Drug: Pemetrexed
• Enrollment: 541

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Nivolumab	Investigator Choice of Chemotherapy
Arm/Group Description	Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity	Administered in 3-week cycles for up to 6 cycles: Squamous: gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or; gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or; paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or; pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
Period Title: Pre-Treatment Period
Started [1]	271	270
Completed [2]	267	263
Not Completed	4	7
Reason Not Completed
Disease Progression	1	1
Participant Withdrew Consent	0	5
Participant no Longer Meets Study Criteria	3	1
[1] Started = Participants Randomized; [2] Completed = Participants Treated
Period Title: Treatment Period
Started	267	263
Received Optional Nivolumab [1]	0	159
Completed	0	28
Not Completed	267	235
Reason Not Completed
Disease progression	189	146
Study drug toxicity	30	34
Death	1	0
Adverse event unrelated to study drug	22	23
Participant request to discontinue study treatment	12	9
Participant withdrew consent	2	2
Maximum clinical benefit	0	18
Poor/Non-compliance	1	0
Administrative reason by sponsor	1	0
Other reasons	9	2
Not Reported	0	1
[1] Participants in the Investigator Choice Arm who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab.

Baseline Characteristics

Arm/Group Title		Nivolumab	Investigator Choice of Chemotherapy	Total
Arm/Group Description		Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity	Administered in 3-week cycles for up to 6 cycles: Squamous: gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or; gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or; paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or; pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.	Total of all reporting groups
Overall Number of Baseline Participants		271	270	541
Baseline Analysis Population Description		All randomized participants
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	271 participants	270 participants	541 participants
		62.8 (10.25)	63.4 (9.63)	63.1 (9.94)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	271 participants	270 participants	541 participants
	Female	87 32.1%	122 45.2%	209 38.6%
	Male	184 67.9%	148 54.8%	332 61.4%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	271 participants	270 participants	541 participants
	Hispanic or Latino	4 1.5%	3 1.1%	7 1.3%
	Not Hispanic or Latino	141 52.0%	139 51.5%	280 51.8%
	Unknown or Not Reported	126 46.5%	128 47.4%	254 47.0%
Race/Ethnicity, Customized [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	271 participants	270 participants	541 participants
White		228	242	470
Black or African American		6	10	16
Asian		30	17	47
American Indian or Alaska Native		1	0	1
Native Hawaiian or Other Pacific Islander		0	0	0
Other		6	1	7
		[1] Measure Description: Race

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival in Participants With PD-L1 Expression >= 5%
Description	Progression-Free Survival (PFS) was defined as the time between the date of randomization and the first date of documented tumor progression, as determined by the Independent Radiology Review Committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause, whichever occurs first. Participants who die without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the day they were randomized. Participants who received subsequent anti-cancer therapy prior to documented progression were censored at the last evaluable tumor assessment prior to the initiation of new therapy.
Time Frame	From date of randomization until date of documented tumor progression (assessed up to August 2016, approximately 28 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 expression levels >= 5%

Arm/Group Title	Nivolumab	Investigator Choice of Chemotherapy
Arm/Group Description:	Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity	Administered in 3-week cycles for up to 6 cycles: Squamous: gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or; gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or; paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or; pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
Overall Number of Participants Analyzed	211	212
Median (95% Confidence Interval); Unit of Measure: Months
	4.21; (2.96 to 5.55)	5.88; (5.42 to 6.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Investigator Choice of Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2511
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Log-rank test stratified by histology (squamous vs. non-squamous) as entered into the IVRS.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.45
	Estimation Comments	Stratified Cox proportional hazard model. Hazard ratio of nivolumab to investigator's choice chemotherapy.

2. Secondary Outcome

Title	Progression-Free Survival in All Randomized Participants
Description	Progression-Free Survival (PFS) was defined as the time between the date of randomization and the first date of documented tumor progression, as determined by the Independent Radiology Review Committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause, whichever occurs first. Participants who die without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the day they were randomized. Participants who received subsequent anti-cancer therapy prior to documented progression were censored at the last evaluable tumor assessment prior to the initiation of new therapy.
Time Frame	From date of randomization until date of documented tumor progression (assessed up to August 2016, approximately 28 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Investigator Choice of Chemotherapy
Arm/Group Description:	Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity	Administered in 3-week cycles for up to 6 cycles: Squamous: gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or; gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or; paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or; pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
Overall Number of Participants Analyzed	271	270
Median (95% Confidence Interval); Unit of Measure: Months
	4.21; (3.06 to 5.52)	5.82; (5.42 to 6.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Investigator Choice of Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.43
	Estimation Comments	Stratified Cox proportional hazard model. Hazard ratio of nivolumab to investigator's choice chemotherapy.

3. Secondary Outcome

Title	Overall Survival in Participants With PD-L1 Expression >= 5%
Description	Overall Survival (OS) was defined as the time from randomization to the date of death. A participant who had not died was censored at the last known alive date. OS was censored at the date of randomization for participants who were randomized but had no follow-up.
Time Frame	From date of randomization to date of death (up to approximately 89 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 expression >= 5%

Arm/Group Title	Nivolumab	Investigator Choice of Chemotherapy
Arm/Group Description:	Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity	Administered in 3-week cycles for up to 6 cycles: Squamous: gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or; gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or; paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or; pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
Overall Number of Participants Analyzed	211	212
Median (95% Confidence Interval); Unit of Measure: Months
	14.36; (11.66 to 17.08)	13.21; (10.81 to 17.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Investigator Choice of Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.20
	Estimation Comments	Stratified Cox proportional hazard model. Hazard ratio of nivolumab to investigator's choice chemotherapy.

4. Secondary Outcome

Title	Overall Survival in All Randomized Participants
Description	Overall Survival (OS) was defined as the time from randomization to the date of death. A participant who had not died was censored at the last known alive date. OS was censored at the date of randomization for participants who were randomized but had no follow-up.
Time Frame	From date of randomization to date of death (up to approximately 89 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Investigator Choice of Chemotherapy
Arm/Group Description:	Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity	Administered in 3-week cycles for up to 6 cycles: Squamous: gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or; gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or; paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or; pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
Overall Number of Participants Analyzed	271	270
Median (95% Confidence Interval); Unit of Measure: Months
	13.73; (11.76 to 15.41)	13.80; (11.01 to 16.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Investigator Choice of Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.24
	Estimation Comments	Stratified Cox proportional hazard model. Hazard ratio of nivolumab to investigator's choice chemotherapy.

5. Secondary Outcome

Title	Objective Response Rate (ORR) in Participants With PD-L1 Expression >= 5%
Description	ORR was defined as the proportion of randomized participants who achieved a Best Overall Response (BOR) of CR or PR using the RECIST v1.1 criteria per Independent Radiology Review Committee (IRRC) assessment. BOR was defined as the best response designation recorded between the date of randomization and the date of objectively documented progression or start of subsequent anti-cancer therapy, whichever occurred first. For participants without documented progression or subsequent therapy, all available response designations contributed to the BOR assessment. For participants who continued treatment beyond progression, BOR was determined from response designations recorded up to the time of initial progression. CR= Disappearance of all evidence of disease, confirmed by PET scan; PR= Regression of measureable disease and no new sites; Stable Disease (SD)= Failure to attain CR/PR or PD; Progressive Disease (PD)= Any new lesion or increase by >=50% of previously involved sites from nadir.
Time Frame	From date of randomization until date of documented tumor progression or subsequent anti-cancer therapy, whichever occurs first (assessed up to August 2016, approximately 28 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 expression >= 5%

Arm/Group Title	Nivolumab	Investigator Choice of Chemotherapy
Arm/Group Description:	Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity	Administered in 3-week cycles for up to 6 cycles: Squamous: gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or; gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or; paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or; pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
Overall Number of Participants Analyzed	211	212
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	26.1; (20.3 to 32.5)	33.5; (27.2 to 40.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Investigator Choice of Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.06
	Estimation Comments	Stratified by histology (squamous vs.non-squamous) at randomization. Strata adjusted odds ratio (Nivolumab over investigator choice of chemotherapy) using Mantel-Haenszel method.

6. Secondary Outcome

Title	Disease-related Symptom Improvement Rate by Week 12
Description	The Lung Cancer Symptom Score (LCSS) is a validated instrument designed to assess the impact of treatment on disease-related symptoms. It consists of 6 symptom-specific questions related to dyspnea, cough, fatigue, pain, hemoptysis and anorexia plus 3 summary items: symptom distress, interference with activity, and global HRQoL. The degree of impairment was recorded on a 100 mm visual analogue scale with scores from 0 to 100 with zero representing the best score. Disease-related symptom improvement rate by Week 12 is defined as the proportion of all randomized (all PD-L1+) participants who had 10 points or more decrease from baseline in average symptom burden index score at any time between randomization and Week 12.
Time Frame	From date of randomization to week 12

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Investigator Choice of Chemotherapy
Arm/Group Description:	Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity	Administered in 3-week cycles for up to 6 cycles: Squamous: gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or; gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or; paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or; pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
Overall Number of Participants Analyzed	271	270
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	35.4; (29.7 to 41.4)	33.7; (28.1 to 39.7)

Adverse Events

Time Frame	Participants were assessed for All-Cause Mortality from the date of their randomization until study completion (up to approximately 89 months). SAEs and Other AEs were assessed from their first dose to 100 days following their last dose (up to approximately 89 months).
Adverse Event Reporting Description	The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
Arm/Group Title	Nivolumab	Investigator Choice of Chemotherapy	Post Chemotherapy Optional Nivolumab
Arm/Group Description	Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity	Administered in 3-week cycles for up to 6 cycles: Squamous: gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or; gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or; paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or; pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.	Participants from the Investigator Choice Arm who progressed during Post-Chemotherapy Phase could receive crossover nivolumab treatment after disease progression. These participants received Nivolumab 3 mg/kg IV infusion every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
All-Cause Mortality
	Nivolumab	Investigator Choice of Chemotherapy	Post Chemotherapy Optional Nivolumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	233/271 (85.98%)	92/270 (34.07%)	136/159 (85.53%)
Serious Adverse Events
	Nivolumab	Investigator Choice of Chemotherapy	Post Chemotherapy Optional Nivolumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	195/267 (73.03%)	203/263 (77.19%)	110/159 (69.18%)
Blood and lymphatic system disorders
Anaemia † 1	1/267 (0.37%)	16/263 (6.08%)	2/159 (1.26%)
Anaemia of malignant disease † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Febrile neutropenia † 1	3/267 (1.12%)	7/263 (2.66%)	1/159 (0.63%)
Haemolytic anaemia † 1	2/267 (0.75%)	0/263 (0.00%)	0/159 (0.00%)
Leukopenia † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Neutropenia † 1	0/267 (0.00%)	4/263 (1.52%)	1/159 (0.63%)
Pancytopenia † 1	1/267 (0.37%)	3/263 (1.14%)	0/159 (0.00%)
Thrombocytopenia † 1	1/267 (0.37%)	6/263 (2.28%)	0/159 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	3/267 (1.12%)	1/263 (0.38%)	0/159 (0.00%)
Acute left ventricular failure † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Atrial fibrillation † 1	1/267 (0.37%)	6/263 (2.28%)	3/159 (1.89%)
Atrial flutter † 1	0/267 (0.00%)	3/263 (1.14%)	2/159 (1.26%)
Atrial tachycardia † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Bradycardia † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Cardiac arrest † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Cardiac failure † 1	2/267 (0.75%)	4/263 (1.52%)	3/159 (1.89%)
Cardiac failure acute † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Cardiac failure congestive † 1	2/267 (0.75%)	1/263 (0.38%)	0/159 (0.00%)
Cardiac tamponade † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Cardiovascular disorder † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Myocardial infarction † 1	0/267 (0.00%)	7/263 (2.66%)	4/159 (2.52%)
Myocardial ischaemia † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Pericardial effusion † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Pericarditis constrictive † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Sinus bradycardia † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Sinus tachycardia † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Congenital, familial and genetic disorders
Tornwaldt cyst † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Endocrine disorders
Adrenal insufficiency † 1	4/267 (1.50%)	4/263 (1.52%)	2/159 (1.26%)
Hypothyroidism † 1	0/267 (0.00%)	2/263 (0.76%)	2/159 (1.26%)
Eye disorders
Angle closure glaucoma † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Cataract † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Exophthalmos † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Glaucoma † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Ophthalmic vein thrombosis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Optic nerve disorder † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Gastrointestinal disorders
Abdominal pain † 1	1/267 (0.37%)	4/263 (1.52%)	1/159 (0.63%)
Ascites † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Colitis † 1	4/267 (1.50%)	3/263 (1.14%)	3/159 (1.89%)
Constipation † 1	2/267 (0.75%)	1/263 (0.38%)	0/159 (0.00%)
Diarrhoea † 1	7/267 (2.62%)	6/263 (2.28%)	4/159 (2.52%)
Dysphagia † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Enteritis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Gastritis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Gastrointestinal haemorrhage † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Ileus † 1	0/267 (0.00%)	3/263 (1.14%)	0/159 (0.00%)
Large intestinal obstruction † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Large intestine perforation † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Nausea † 1	4/267 (1.50%)	5/263 (1.90%)	1/159 (0.63%)
Oesophagitis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Small intestinal haemorrhage † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Small intestinal obstruction † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Upper gastrointestinal haemorrhage † 1	1/267 (0.37%)	1/263 (0.38%)	1/159 (0.63%)
Vomiting † 1	4/267 (1.50%)	5/263 (1.90%)	1/159 (0.63%)
General disorders
Asthenia † 1	2/267 (0.75%)	0/263 (0.00%)	0/159 (0.00%)
Catheter site pain † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Chest pain † 1	2/267 (0.75%)	2/263 (0.76%)	0/159 (0.00%)
Death † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Fatigue † 1	2/267 (0.75%)	8/263 (3.04%)	3/159 (1.89%)
General physical health deterioration † 1	4/267 (1.50%)	6/263 (2.28%)	4/159 (2.52%)
Illness † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Localised oedema † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Multiple organ dysfunction syndrome † 1	2/267 (0.75%)	0/263 (0.00%)	0/159 (0.00%)
Oedema peripheral † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Pain † 1	1/267 (0.37%)	3/263 (1.14%)	1/159 (0.63%)
Performance status decreased † 1	0/267 (0.00%)	2/263 (0.76%)	0/159 (0.00%)
Pyrexia † 1	7/267 (2.62%)	9/263 (3.42%)	6/159 (3.77%)
Sudden death † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Hepatobiliary disorders
Bile duct stenosis † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Cholecystitis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Cholecystitis acute † 1	2/267 (0.75%)	1/263 (0.38%)	1/159 (0.63%)
Cholelithiasis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Cholestasis † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Drug-induced liver injury † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Gallbladder obstruction † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Hepatic failure † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Hepatitis † 1	1/267 (0.37%)	1/263 (0.38%)	1/159 (0.63%)
Hepatitis acute † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Hypertransaminasaemia † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Jaundice † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Immune system disorders
Hypersensitivity † 1	3/267 (1.12%)	0/263 (0.00%)	0/159 (0.00%)
Infections and infestations
Appendicitis † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Appendicitis perforated † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Bronchitis † 1	2/267 (0.75%)	3/263 (1.14%)	1/159 (0.63%)
Cellulitis † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Diverticulitis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Erysipelas † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Gastroenteritis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Herpes virus infection † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Infection † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Influenza † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Localised infection † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Lower respiratory tract infection † 1	2/267 (0.75%)	1/263 (0.38%)	1/159 (0.63%)
Nasopharyngitis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Norovirus infection † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Oral candidiasis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Peritonitis † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Pleural infection † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Pneumonia † 1	21/267 (7.87%)	26/263 (9.89%)	8/159 (5.03%)
Pneumonia aspiration † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Pneumonia bacterial † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Post procedural infection † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Pulmonary sepsis † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Respiratory tract infection † 1	1/267 (0.37%)	2/263 (0.76%)	1/159 (0.63%)
Sepsis † 1	5/267 (1.87%)	5/263 (1.90%)	3/159 (1.89%)
Septic shock † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Skin infection † 1	0/267 (0.00%)	2/263 (0.76%)	0/159 (0.00%)
Subcutaneous abscess † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Upper respiratory tract infection † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Urinary tract infection † 1	3/267 (1.12%)	2/263 (0.76%)	2/159 (1.26%)
Vascular device infection † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Wound infection † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Injury, poisoning and procedural complications
Compression fracture † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Fall † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Femoral neck fracture † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Femur fracture † 1	0/267 (0.00%)	2/263 (0.76%)	0/159 (0.00%)
Hip fracture † 1	2/267 (0.75%)	0/263 (0.00%)	0/159 (0.00%)
Infusion related reaction † 1	2/267 (0.75%)	0/263 (0.00%)	0/159 (0.00%)
Joint dislocation † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Kyphosis postoperative † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Lumbar vertebral fracture † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Procedural pneumothorax † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Radiation necrosis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Radiation pneumonitis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Road traffic accident † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Spinal compression fracture † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Upper limb fracture † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Vascular procedure complication † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Investigations
Alanine aminotransferase increased † 1	5/267 (1.87%)	1/263 (0.38%)	1/159 (0.63%)
Aspartate aminotransferase increased † 1	6/267 (2.25%)	2/263 (0.76%)	2/159 (1.26%)
Blood alkaline phosphatase increased † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Blood bilirubin increased † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Blood creatine phosphokinase increased † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Blood creatinine increased † 1	2/267 (0.75%)	1/263 (0.38%)	0/159 (0.00%)
C-reactive protein increased † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Gamma-glutamyltransferase increased † 1	2/267 (0.75%)	0/263 (0.00%)	0/159 (0.00%)
General physical condition abnormal † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Haemoglobin decreased † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Transaminases increased † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	4/267 (1.50%)	5/263 (1.90%)	3/159 (1.89%)
Diabetes mellitus † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Hypercalcaemia † 1	3/267 (1.12%)	3/263 (1.14%)	3/159 (1.89%)
Hyperglycaemia † 1	2/267 (0.75%)	2/263 (0.76%)	2/159 (1.26%)
Hypoglycaemia † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Hypokalaemia † 1	1/267 (0.37%)	1/263 (0.38%)	1/159 (0.63%)
Hyponatraemia † 1	5/267 (1.87%)	4/263 (1.52%)	2/159 (1.26%)
Metabolic acidosis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Back pain † 1	2/267 (0.75%)	3/263 (1.14%)	1/159 (0.63%)
Bone pain † 1	1/267 (0.37%)	2/263 (0.76%)	0/159 (0.00%)
Muscular weakness † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Musculoskeletal chest pain † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Osteolysis † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Osteonecrosis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Pain in extremity † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Pathological fracture † 1	2/267 (0.75%)	0/263 (0.00%)	0/159 (0.00%)
Polyarthritis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Spinal stenosis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Cancer pain † 1	8/267 (3.00%)	2/263 (0.76%)	1/159 (0.63%)
Chronic myeloid leukaemia † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Follicular lymphoma † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Haemangioblastoma † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Intestinal metastasis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Lung cancer metastatic † 1	0/267 (0.00%)	2/263 (0.76%)	2/159 (1.26%)
Lung neoplasm malignant † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Malignant melanoma † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Malignant neoplasm progression † 1	69/267 (25.84%)	95/263 (36.12%)	55/159 (34.59%)
Malignant pleural effusion † 1	4/267 (1.50%)	5/263 (1.90%)	3/159 (1.89%)
Mesothelioma malignant † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Metastases to bone † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Metastases to central nervous system † 1	2/267 (0.75%)	8/263 (3.04%)	6/159 (3.77%)
Metastases to liver † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Metastases to meninges † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Metastases to spine † 1	3/267 (1.12%)	0/263 (0.00%)	0/159 (0.00%)
Neoplasm progression † 1	1/267 (0.37%)	2/263 (0.76%)	0/159 (0.00%)
Non-small cell lung cancer † 1	2/267 (0.75%)	1/263 (0.38%)	1/159 (0.63%)
Non-small cell lung cancer metastatic † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Pericardial effusion malignant † 1	5/267 (1.87%)	2/263 (0.76%)	0/159 (0.00%)
Tumour associated fever † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Tumour pain † 1	4/267 (1.50%)	2/263 (0.76%)	1/159 (0.63%)
Nervous system disorders
Aphasia † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Ataxia † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Cerebral infarction † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Cerebrovascular accident † 1	2/267 (0.75%)	1/263 (0.38%)	0/159 (0.00%)
Cubital tunnel syndrome † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Depressed level of consciousness † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Epilepsy † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Headache † 1	2/267 (0.75%)	0/263 (0.00%)	0/159 (0.00%)
IIIrd nerve paresis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Ischaemic stroke † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Loss of consciousness † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Malignant spinal cord compression † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Muscle spasticity † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Nervous system disorder † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Peripheral motor neuropathy † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Presyncope † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Seizure † 1	4/267 (1.50%)	3/263 (1.14%)	1/159 (0.63%)
Spinal cord compression † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Syncope † 1	4/267 (1.50%)	3/263 (1.14%)	0/159 (0.00%)
VIth nerve paresis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Vocal cord paralysis † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Product Issues
Device occlusion † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Psychiatric disorders
Alcohol withdrawal syndrome † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Confusional state † 1	3/267 (1.12%)	2/263 (0.76%)	1/159 (0.63%)
Disorientation † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Mental status changes † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Organic brain syndrome † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Psychotic disorder † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Suicide attempt † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	2/267 (0.75%)	0/263 (0.00%)	0/159 (0.00%)
Haematuria † 1	1/267 (0.37%)	1/263 (0.38%)	1/159 (0.63%)
Hydronephrosis † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Oliguria † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Renal failure † 1	2/267 (0.75%)	1/263 (0.38%)	1/159 (0.63%)
Renal infarct † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Tubulointerstitial nephritis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Aspiration † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Asthma † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Atelectasis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Bronchial obstruction † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Chronic obstructive pulmonary disease † 1	3/267 (1.12%)	7/263 (2.66%)	1/159 (0.63%)
Cough † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Dyspnoea † 1	6/267 (2.25%)	9/263 (3.42%)	5/159 (3.14%)
Dyspnoea exertional † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Eosinophilic pneumonia † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Haemoptysis † 1	0/267 (0.00%)	2/263 (0.76%)	1/159 (0.63%)
Haemothorax † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Hypoxia † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Interstitial lung disease † 1	1/267 (0.37%)	1/263 (0.38%)	1/159 (0.63%)
Laryngeal haemorrhage † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Lung infiltration † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Mediastinal disorder † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Obstructive airways disorder † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Pleural effusion † 1	8/267 (3.00%)	5/263 (1.90%)	3/159 (1.89%)
Pleuritic pain † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Pneumonitis † 1	9/267 (3.37%)	2/263 (0.76%)	1/159 (0.63%)
Pneumothorax † 1	4/267 (1.50%)	2/263 (0.76%)	2/159 (1.26%)
Pulmonary embolism † 1	8/267 (3.00%)	11/263 (4.18%)	5/159 (3.14%)
Pulmonary haemorrhage † 1	2/267 (0.75%)	1/263 (0.38%)	0/159 (0.00%)
Pulmonary mass † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Pulmonary microemboli † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Pulmonary oedema † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Respiratory failure † 1	4/267 (1.50%)	2/263 (0.76%)	2/159 (1.26%)
Skin and subcutaneous tissue disorders
Rash † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Rash maculo-papular † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Rash papular † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Stevens-Johnson syndrome † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Vascular disorders
Air embolism † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Aortic aneurysm rupture † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Circulatory collapse † 1	0/267 (0.00%)	3/263 (1.14%)	1/159 (0.63%)
Deep vein thrombosis † 1	3/267 (1.12%)	1/263 (0.38%)	1/159 (0.63%)
Embolism † 1	0/267 (0.00%)	4/263 (1.52%)	1/159 (0.63%)
Extremity necrosis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Hypotension † 1	1/267 (0.37%)	1/263 (0.38%)	0/159 (0.00%)
Iliac artery occlusion † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Jugular vein thrombosis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Leriche syndrome † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Lymphoedema † 1	0/267 (0.00%)	1/263 (0.38%)	1/159 (0.63%)
Peripheral artery thrombosis † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Peripheral ischaemia † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Superior vena cava syndrome † 1	0/267 (0.00%)	2/263 (0.76%)	0/159 (0.00%)
Vascular occlusion † 1	0/267 (0.00%)	1/263 (0.38%)	0/159 (0.00%)
Vein disorder † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
Venous thrombosis † 1	1/267 (0.37%)	0/263 (0.00%)	0/159 (0.00%)
1 Term from vocabulary, 25.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Nivolumab	Investigator Choice of Chemotherapy	Post Chemotherapy Optional Nivolumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	245/267 (91.76%)	252/263 (95.82%)	137/159 (86.16%)
Blood and lymphatic system disorders
Anaemia † 1	54/267 (20.22%)	142/263 (53.99%)	38/159 (23.90%)
Leukopenia † 1	1/267 (0.37%)	17/263 (6.46%)	1/159 (0.63%)
Neutropenia † 1	5/267 (1.87%)	54/263 (20.53%)	4/159 (2.52%)
Thrombocytopenia † 1	5/267 (1.87%)	40/263 (15.21%)	4/159 (2.52%)
Endocrine disorders
Hypothyroidism † 1	23/267 (8.61%)	23/263 (8.75%)	14/159 (8.81%)
Eye disorders
Lacrimation increased † 1	3/267 (1.12%)	21/263 (7.98%)	1/159 (0.63%)
Gastrointestinal disorders
Abdominal pain † 1	35/267 (13.11%)	32/263 (12.17%)	12/159 (7.55%)
Abdominal pain upper † 1	11/267 (4.12%)	23/263 (8.75%)	9/159 (5.66%)
Constipation † 1	65/267 (24.34%)	84/263 (31.94%)	24/159 (15.09%)
Diarrhoea † 1	84/267 (31.46%)	82/263 (31.18%)	29/159 (18.24%)
Dry mouth † 1	13/267 (4.87%)	12/263 (4.56%)	8/159 (5.03%)
Dyspepsia † 1	19/267 (7.12%)	13/263 (4.94%)	2/159 (1.26%)
Nausea † 1	86/267 (32.21%)	149/263 (56.65%)	36/159 (22.64%)
Stomatitis † 1	13/267 (4.87%)	20/263 (7.60%)	5/159 (3.14%)
Vomiting † 1	59/267 (22.10%)	77/263 (29.28%)	16/159 (10.06%)
General disorders
Asthenia † 1	26/267 (9.74%)	41/263 (15.59%)	13/159 (8.18%)
Chest pain † 1	9/267 (3.37%)	25/263 (9.51%)	9/159 (5.66%)
Chills † 1	18/267 (6.74%)	18/263 (6.84%)	6/159 (3.77%)
Fatigue † 1	108/267 (40.45%)	134/263 (50.95%)	47/159 (29.56%)
Malaise † 1	15/267 (5.62%)	14/263 (5.32%)	5/159 (3.14%)
Mucosal inflammation † 1	7/267 (2.62%)	23/263 (8.75%)	3/159 (1.89%)
Non-cardiac chest pain † 1	25/267 (9.36%)	21/263 (7.98%)	11/159 (6.92%)
Oedema peripheral † 1	35/267 (13.11%)	67/263 (25.48%)	21/159 (13.21%)
Pain † 1	14/267 (5.24%)	12/263 (4.56%)	9/159 (5.66%)
Pyrexia † 1	37/267 (13.86%)	55/263 (20.91%)	22/159 (13.84%)
Infections and infestations
Bronchitis † 1	13/267 (4.87%)	19/263 (7.22%)	10/159 (6.29%)
Nasopharyngitis † 1	19/267 (7.12%)	20/263 (7.60%)	10/159 (6.29%)
Pneumonia † 1	25/267 (9.36%)	23/263 (8.75%)	9/159 (5.66%)
Upper respiratory tract infection † 1	24/267 (8.99%)	24/263 (9.13%)	9/159 (5.66%)
Urinary tract infection † 1	14/267 (5.24%)	13/263 (4.94%)	4/159 (2.52%)
Injury, poisoning and procedural complications
Fall † 1	15/267 (5.62%)	11/263 (4.18%)	5/159 (3.14%)
Investigations
Alanine aminotransferase increased † 1	31/267 (11.61%)	30/263 (11.41%)	13/159 (8.18%)
Aspartate aminotransferase increased † 1	39/267 (14.61%)	28/263 (10.65%)	10/159 (6.29%)
Blood alkaline phosphatase increased † 1	22/267 (8.24%)	18/263 (6.84%)	7/159 (4.40%)
Blood creatinine increased † 1	13/267 (4.87%)	34/263 (12.93%)	17/159 (10.69%)
Gamma-glutamyltransferase increased † 1	10/267 (3.75%)	14/263 (5.32%)	4/159 (2.52%)
Lymphocyte count decreased † 1	18/267 (6.74%)	18/263 (6.84%)	5/159 (3.14%)
Neutrophil count decreased † 1	9/267 (3.37%)	43/263 (16.35%)	4/159 (2.52%)
Platelet count decreased † 1	12/267 (4.49%)	38/263 (14.45%)	1/159 (0.63%)
Weight decreased † 1	42/267 (15.73%)	37/263 (14.07%)	12/159 (7.55%)
White blood cell count decreased † 1	7/267 (2.62%)	33/263 (12.55%)	6/159 (3.77%)
Metabolism and nutrition disorders
Decreased appetite † 1	91/267 (34.08%)	102/263 (38.78%)	37/159 (23.27%)
Dehydration † 1	10/267 (3.75%)	19/263 (7.22%)	7/159 (4.40%)
Hyperglycaemia † 1	19/267 (7.12%)	18/263 (6.84%)	10/159 (6.29%)
Hyperkalaemia † 1	15/267 (5.62%)	19/263 (7.22%)	11/159 (6.92%)
Hypoalbuminaemia † 1	28/267 (10.49%)	27/263 (10.27%)	11/159 (6.92%)
Hypokalaemia † 1	24/267 (8.99%)	31/263 (11.79%)	13/159 (8.18%)
Hypomagnesaemia † 1	16/267 (5.99%)	49/263 (18.63%)	19/159 (11.95%)
Hyponatraemia † 1	28/267 (10.49%)	37/263 (14.07%)	13/159 (8.18%)
Hypophosphataemia † 1	6/267 (2.25%)	17/263 (6.46%)	6/159 (3.77%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	53/267 (19.85%)	47/263 (17.87%)	29/159 (18.24%)
Back pain † 1	42/267 (15.73%)	62/263 (23.57%)	23/159 (14.47%)
Muscle spasms † 1	9/267 (3.37%)	14/263 (5.32%)	10/159 (6.29%)
Muscular weakness † 1	17/267 (6.37%)	26/263 (9.89%)	9/159 (5.66%)
Musculoskeletal chest pain † 1	18/267 (6.74%)	13/263 (4.94%)	5/159 (3.14%)
Myalgia † 1	28/267 (10.49%)	28/263 (10.65%)	10/159 (6.29%)
Pain in extremity † 1	23/267 (8.61%)	31/263 (11.79%)	11/159 (6.92%)
Nervous system disorders
Dizziness † 1	30/267 (11.24%)	41/263 (15.59%)	21/159 (13.21%)
Dysgeusia † 1	14/267 (5.24%)	25/263 (9.51%)	7/159 (4.40%)
Headache † 1	30/267 (11.24%)	50/263 (19.01%)	19/159 (11.95%)
Neuropathy peripheral † 1	5/267 (1.87%)	15/263 (5.70%)	8/159 (5.03%)
Peripheral sensory neuropathy † 1	7/267 (2.62%)	24/263 (9.13%)	7/159 (4.40%)
Psychiatric disorders
Anxiety † 1	17/267 (6.37%)	18/263 (6.84%)	12/159 (7.55%)
Depression † 1	14/267 (5.24%)	13/263 (4.94%)	4/159 (2.52%)
Insomnia † 1	24/267 (8.99%)	40/263 (15.21%)	18/159 (11.32%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	77/267 (28.84%)	79/263 (30.04%)	37/159 (23.27%)
Dysphonia † 1	12/267 (4.49%)	21/263 (7.98%)	3/159 (1.89%)
Dyspnoea † 1	69/267 (25.84%)	75/263 (28.52%)	38/159 (23.90%)
Epistaxis † 1	8/267 (3.00%)	22/263 (8.37%)	4/159 (2.52%)
Haemoptysis † 1	17/267 (6.37%)	20/263 (7.60%)	8/159 (5.03%)
Oropharyngeal pain † 1	8/267 (3.00%)	15/263 (5.70%)	5/159 (3.14%)
Pleural effusion † 1	8/267 (3.00%)	16/263 (6.08%)	9/159 (5.66%)
Pneumonitis † 1	12/267 (4.49%)	17/263 (6.46%)	15/159 (9.43%)
Productive cough † 1	30/267 (11.24%)	25/263 (9.51%)	8/159 (5.03%)
Skin and subcutaneous tissue disorders
Alopecia † 1	9/267 (3.37%)	26/263 (9.89%)	3/159 (1.89%)
Dry skin † 1	22/267 (8.24%)	26/263 (9.89%)	14/159 (8.81%)
Pruritus † 1	39/267 (14.61%)	31/263 (11.79%)	17/159 (10.69%)
Rash † 1	39/267 (14.61%)	37/263 (14.07%)	20/159 (12.58%)
Rash maculo-papular † 1	18/267 (6.74%)	12/263 (4.56%)	6/159 (3.77%)
Vascular disorders
Hypertension † 1	18/267 (6.74%)	19/263 (7.22%)	8/159 (5.03%)
Hypotension † 1	9/267 (3.37%)	14/263 (5.32%)	8/159 (5.03%)
1 Term from vocabulary, 25.0; † 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):

Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR Jr, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA; CheckMate 026 Investigators. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426. doi: 10.1056/NEJMoa1613493.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02041533
• Other Study ID Numbers: CA209-026; 2012-004502-93 ( EudraCT Number )
• First Submitted: January 19, 2014
• First Posted: January 22, 2014
• Results First Submitted: June 26, 2017
• Results First Posted: July 26, 2017
• Last Update Posted: March 2, 2023