An Investigational Immuno-therapy Study to Investigate the Safety and Effectiveness of Nivolumab, and Nivolumab Combination Therapy in Virus-associated Tumors (CheckMate358)

• ClinicalTrials.gov Identifier: NCT02488759
• Recruitment Status: Completed
• First Posted: July 2, 2015
• Results First Posted: April 12, 2022
• Last Update Posted: November 13, 2023
• Sponsor: Bristol-Myers Squibb
• Collaborator: Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Bristol-Myers Squibb

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Various Advanced Cancer
• Interventions: Drug: Nivolumab; Drug: Ipilimumab; Drug: Relatlimab; Drug: Daratumumab
• Enrollment: 578

Participant Flow

Recruitment Details
Pre-assignment Details	578 participants treated

Arm/Group Title	Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D	Neoadjuvant
Arm/Group Description	Nivolumab IV over 30 minutes at 240 mg every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks + Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 1 mg/kg IV over 30 minutes + Ipilimumab 3 mg/kg IV over 30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 240 mg IV over 30 minutes + BMS-986016 (Relatlimab) 80 mg IV over 60 minutes administered every 2 weeks for a maximum of 24 months, or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Daratumumab 16 mg/kg IV weekly for the first 8 weeks. Starting at Week 3, Nivolumab 240 mg IV over 30 minutes every 2 weeks. Daratumumab 16 mg/kg every 2 weeks from Weeks 9-24. Starting at Week 25, Nivolumab 480 mg IV flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab administered intravenously (IV) over 30 minutes at 240 mg for 2 doses, on Day 1 and Day 15
Period Title: Overall Study
Started [1]	113	195	133	8	6	123
Completed [2]	0	0	0	0	0	116
Not Completed	113	195	133	8	6	7
Reason Not Completed
Disease progression	73	111	62	7	4	2
Study drug toxicity	11	33	31	0	0	2
Adverse event unrelated to study drug	9	11	7	0	1	0
Participant request to discontinue study treatment	6	8	4	0	0	0
Withdrawal by Subject	4	0	3	0	0	2
Lost to Follow-up	0	0	2	0	0	0
Maximum clinical benefit	3	0	1	0	0	0
Other reasons	7	32	23	1	1	1
[1] Started = treated; [2] Completed = completed the treatment period

Baseline Characteristics

Arm/Group Title		Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D	Neoadjuvant	Total
Arm/Group Description		Nivolumab IV over 30 minutes at 240 mg every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks + Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 1 mg/kg IV over 30 minutes + Ipilimumab 3 mg/kg IV over 30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 240 mg IV over 30 minutes + BMS-986016 (Relatlimab) 80 mg IV over 60 minutes administered every 2 weeks for a maximum of 24 months, or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Daratumumab 16 mg/kg IV weekly for the first 8 weeks. Starting at Week 3, Nivolumab 240 mg IV over 30 minutes every 2 weeks. Daratumumab 16 mg/kg every 2 weeks from Weeks 9-24. Starting at Week 25, Nivolumab 480 mg IV flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab administered intravenously (IV) over 30 minutes at 240 mg for 2 doses, on Day 1 and Day 15	Total of all reporting groups
Overall Number of Baseline Participants		113	195	133	8	6	123	578
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	113 participants	195 participants	133 participants	8 participants	6 participants	123 participants	578 participants
		57.4 (13.5)	57.5 (13.2)	48.2 (12.3)	59.0 (7.6)	66.5 (15.3)	62.0 (12.7)	56.4 (13.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	113 participants	195 participants	133 participants	8 participants	6 participants	123 participants	578 participants
	Female	39 34.5%	85 43.6%	129 97.0%	1 12.5%	3 50.0%	59 48.0%	316 54.7%
	Male	74 65.5%	110 56.4%	4 3.0%	7 87.5%	3 50.0%	64 52.0%	262 45.3%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	113 participants	195 participants	133 participants	8 participants	6 participants	123 participants	578 participants
	American Indian or Alaska Native	2 1.8%	0 0.0%	2 1.5%	0 0.0%	0 0.0%	2 1.6%	6 1.0%
	Asian	14 12.4%	31 15.9%	10 7.5%	0 0.0%	0 0.0%	1 0.8%	56 9.7%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	3 2.7%	6 3.1%	5 3.8%	0 0.0%	0 0.0%	3 2.4%	17 2.9%
	White	86 76.1%	147 75.4%	115 86.5%	8 100.0%	6 100.0%	113 91.9%	475 82.2%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	8 7.1%	11 5.6%	1 0.8%	0 0.0%	0 0.0%	4 3.3%	24 4.2%

Outcome Measures

1. Primary Outcome

Title	Neoadjuvant: Number of Participants With Drug-Related Select Adverse Events (AEs)
Description	Number of participants with any grade of drug-related select adverse events (AEs) including endocrine, gastrointestinal, hepatic, pulmonary, renal, skin, and hypersensitivity AEs in Neoadjuvant cohort
Time Frame	From first dose to 30 days post last dose (Up to 2 months)

Outcome Measure Data

Analysis Population Description

All treated participants in the neoadjuvant cohort

Arm/Group Title	Neoadjuvant
Arm/Group Description:	Nivolumab administered intravenously (IV) over 30 minutes at 240 mg for 2 doses, on Day 1 and Day 15
Overall Number of Participants Analyzed	123
Measure Type: Count of Participants; Unit of Measure: Participants
Endocrine AEs	3 2.4%
Gastrointestinal AEs	4 3.3%
Hepatic AEs	3 2.4%
Pulmonary AEs	0 0.0%
Renal AEs	0 0.0%
Skin AEs	9 7.3%
Hypersensitivity/Infusion Reaction AEs	5 4.1%

2. Primary Outcome

Title	Neoadjuvant: Number of Participants With Drug-Related Serious Adverse Events (SAEs)
Description	Number of participants with any grade of drug-related serious adverse events (SAEs) in Neoadjuvant cohort
Time Frame	From first dose to 30 days post last dose (Up to 2 months)

Outcome Measure Data

Analysis Population Description

All treated participants in the neoadjuvant cohort

Arm/Group Title	Neoadjuvant
Arm/Group Description:	Nivolumab administered intravenously (IV) over 30 minutes at 240 mg for 2 doses, on Day 1 and Day 15
Overall Number of Participants Analyzed	123
Measure Type: Count of Participants; Unit of Measure: Participants
	6 4.9%

3. Primary Outcome

Title	Neoadjuvant: Rate of Surgery Delay
Description	Rate of surgery delay is defined as the percentage of participants in the neoadjuvant cohort with surgery delayed > 4 weeks from the planned surgery date or planned start date for chemoradiation due to a drug-related adverse event. Participants with the following diseases will be assessed: HPV positive squamous cell carcinoma of the Head and Neck (SCCHN);; HPV negative SCCHN;; Cervical Carcinoma;; Vaginal/Vulvar Carcinoma;; Merkel Cell Carcinoma
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

All tumor reduction evaluable participants in the neoadjuvant cohort

Arm/Group Title		Neoadjuvant
Arm/Group Description:		Nivolumab administered intravenously (IV) over 30 minutes at 240 mg for 2 doses, on Day 1 and Day 15
Overall Number of Participants Analyzed		112
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
HPV positive SCCHN	Number Analyzed	25 participants
		0; (0 to 13.7)
HPV negative SCCHN	Number Analyzed	25 participants
		0; (0 to 13.7)
Cervical Carcinoma	Number Analyzed	13 participants
		7.7; (0.2 to 36.0)
Vaginal/Vulvar Carcinoma	Number Analyzed	12 participants
		0; (0.0 to 26.5)
Merkel Cell Carcinoma	Number Analyzed	37 participants
		2.7; (0.1 to 14.2)

4. Primary Outcome

Title	Metastatic: Investigator-Assessed Objective Response Rate (ORR)
Description	Objective response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) using RECIST 1.1 criteria. An ORR in excess of 10% will be considered of clinical interest, and an ORR of 25% or greater will be considered of strong clinical interest. 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. Participants with the following diseases will be assessed: EBV positive related gastric cancer;; HPV positive SCCHN;; Other anogenital HPV associated cancers;; GYN (Cervical, Vaginal, Vulvar) carcinoma;; Merkel cell carcinoma (MCC);; Nasopharyngeal carcinoma (NPC)
Time Frame	From the date of first dose to the date of the initial objectively documented tumor progression or the date of the last tumor assessment prior to subsequent therapy (Up to 65 months)

Outcome Measure Data

Analysis Population Description

All treated participants in the metastatic cohorts

Arm/Group Title		Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D
Arm/Group Description:		Nivolumab IV over 30 minutes at 240 mg every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks + Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 1 mg/kg IV over 30 minutes + Ipilimumab 3 mg/kg IV over 30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 240 mg IV over 30 minutes + BMS-986016 (Relatlimab) 80 mg IV over 60 minutes administered every 2 weeks for a maximum of 24 months, or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Daratumumab 16 mg/kg IV weekly for the first 8 weeks. Starting at Week 3, Nivolumab 240 mg IV over 30 minutes every 2 weeks. Daratumumab 16 mg/kg every 2 weeks from Weeks 9-24. Starting at Week 25, Nivolumab 480 mg IV flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of consent, whichever comes first
Overall Number of Participants Analyzed		113	195	133	8	6
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
EBV positive related gastric cancer	Number Analyzed	14 participants	0 participants	0 participants	0 participants	0 participants
		14.3; (1.8 to 42.8)
HPV positive SCCHN	Number Analyzed	26 participants	42 participants	0 participants	8 participants	0 participants
		11.5; (2.4 to 30.2)	31.0; (17.6 to 47.1)		0; (0.0 to 36.9)
Other anogenital HPV associated cancers	Number Analyzed	0 participants	23 participants	21 participants	0 participants	0 participants
			34.8; (16.4 to 57.3)	28.6; (11.3 to 52.2)
SCCHN I-O naive	Number Analyzed	0 participants	0 participants	0 participants	0 participants	6 participants
						16.7; (0.4 to 64.1)
Cervical	Number Analyzed	19 participants	45 participants	45 participants	0 participants	0 participants
		26.3; (9.1 to 51.2)	31.1; (18.2 to 46.6)	40.0; (25.7 to 55.7)
Cervical first line	Number Analyzed	0 participants	0 participants	44 participants	0 participants	0 participants
				36.4; (22.4 to 52.2)
Cervical second line	Number Analyzed	0 participants	0 participants	23 participants	0 participants	0 participants
				39.1; (19.7 to 61.5)
Vaginal/Vulvar	Number Analyzed	5 participants	0 participants	0 participants	0 participants	0 participants
		20.0; (0.5 to 71.6)
MCC	Number Analyzed	25 participants	43 participants	0 participants	0 participants	0 participants
		64.0; (42.5 to 82.0)	58.1; (42.1 to 73.0)
NPC	Number Analyzed	24 participants	42 participants	0 participants	0 participants	0 participants
		16.7; (4.7 to 37.4)	26.2; (13.9 to 42.0)

5. Secondary Outcome

Title	Metastatic: Investigator-Assessed Duration of Response (DoR)
Description	Duration of response (DoR) is defined as the time from first confirmed response (complete response or partial response) to the date of the initial objectively documented tumor progression as determined per investigator assessment using RECIST 1.1 criteria or death due to any cause, whichever occurs first. Participants with the following diseases will be assessed: EBV positive related gastric cancer;; HPV positive SCCHN;; Other anogenital HPV associated cancers;; GYN (Cervical, Vaginal, Vulvar) carcinoma;; Merkel cell carcinoma (MCC);; Nasopharyngeal carcinoma (NPC) NOTE: "Cervical, Randomized" and "Cervical, Pooled" are not mutually exclusive categories.
Time Frame	From first confirmed response (complete response or partial response) to the date of the initial objectively documented tumor progression or death due to any cause, whichever occurs first (Up to 83 months)

Outcome Measure Data

Analysis Population Description

All complete and partial responders in the metastatic cohorts

Arm/Group Title		Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D
Arm/Group Description:		Nivolumab IV over 30 minutes at 240 mg every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks + Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 1 mg/kg IV over 30 minutes + Ipilimumab 3 mg/kg IV over 30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 240 mg IV over 30 minutes + BMS-986016 (Relatlimab) 80 mg IV over 60 minutes administered every 2 weeks for a maximum of 24 months, or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Daratumumab 16 mg/kg IV weekly for the first 8 weeks. Starting at Week 3, Nivolumab 240 mg IV over 30 minutes every 2 weeks. Daratumumab 16 mg/kg every 2 weeks from Weeks 9-24. Starting at Week 25, Nivolumab 480 mg IV flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of consent, whichever comes first
Overall Number of Participants Analyzed		30	72	50	0	1
Median (95% Confidence Interval); Unit of Measure: Months
EBV positive related gastric cancer	Number Analyzed	2 participants	0 participants	0 participants	0 participants	0 participants
		NA [1]; (NA to NA)
HPV positive SCCHN	Number Analyzed	3 participants	13 participants	0 participants	0 participants	0 participants
		44.25 [2]; (24.90 to NA)	34.46 [2]; (10.45 to NA)
Other anogenital HPV associated cancers	Number Analyzed	0 participants	8 participants	5 participants	0 participants	0 participants
			18.23; (3.68 to 27.93)	3.71 [2]; (3.58 to NA)
SCCHN I-O naive	Number Analyzed	0 participants	0 participants	0 participants	0 participants	1 participants
						NA [1]; (NA to NA)
Cervical, Randomized	Number Analyzed	5 participants	14 participants	18 participants	0 participants	0 participants
		NA [3]; (35.29 to NA)	NA [3]; (8.67 to NA)	34.07 [2]; (15.28 to NA)
Cervical, Pooled	Number Analyzed	0 participants	0 participants	45 participants	0 participants	0 participants
				34.07 [2]; (15.28 to NA)
Vaginal/Vulvar	Number Analyzed	1 participants	0 participants	0 participants	0 participants	0 participants
		4.96 [4]; (NA to NA)
MCC	Number Analyzed	15 participants	25 participants	0 participants	0 participants	0 participants
		60.62 [2]; (16.72 to NA)	25.86 [2]; (10.38 to NA)
NPC	Number Analyzed	4 participants	12 participants	0 participants	0 participants	0 participants
		9.46 [2]; (3.68 to NA)	19.63 [2]; (5.55 to NA)

[1]

Median not reached as insufficient progression events among responders

[2]

Upper limit not calculable as upper CI bound does not cross 50% threshold

[3]

Median not reached as insufficient progression events among responders and Upper limit not calculable as upper CI bound does not cross 50% threshold

[4]

Lower limit and Upper limit not calculable as upper CI bound does not cross 50% threshold

6. Secondary Outcome

Title	Metastatic: Overall Survival (OS)
Description	Overall survival (OS) is defined as the time from first dosing date to the date of death. A participant who has not died will be censored at last known date alive. Participants with the following diseases will be assessed: EBV positive related gastric cancer;; HPV positive SCCHN;; Other anogenital HPV associated cancers;; GYN (Cervical, Vaginal, Vulvar) carcinoma;; Merkel cell carcinoma (MCC);; Nasopharyngeal carcinoma (NPC) Note: "Cervical, Randomized" and "Cervical, Pooled" are not mutually exclusive categories
Time Frame	From the first dosing date to the date of death (Up to 83 months)

Outcome Measure Data

Analysis Population Description

All treated participants in the metastatic cohorts

Arm/Group Title		Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D
Arm/Group Description:		Nivolumab IV over 30 minutes at 240 mg every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks + Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 1 mg/kg IV over 30 minutes + Ipilimumab 3 mg/kg IV over 30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 240 mg IV over 30 minutes + BMS-986016 (Relatlimab) 80 mg IV over 60 minutes administered every 2 weeks for a maximum of 24 months, or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Daratumumab 16 mg/kg IV weekly for the first 8 weeks. Starting at Week 3, Nivolumab 240 mg IV over 30 minutes every 2 weeks. Daratumumab 16 mg/kg every 2 weeks from Weeks 9-24. Starting at Week 25, Nivolumab 480 mg IV flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of consent, whichever comes first
Overall Number of Participants Analyzed		113	195	133	8	6
Median (95% Confidence Interval); Unit of Measure: Months
EBV positive related gastric cancer	Number Analyzed	14 participants	0 participants	0 participants	0 participants	0 participants
		9.99; (3.09 to 30.13)
HPV positive SCCHN	Number Analyzed	26 participants	42 participants	0 participants	8 participants	0 participants
		20.44; (13.90 to 36.50)	17.08; (9.49 to 26.78)		8.84; (2.50 to 35.06)
Other anogenital HPV associated cancers	Number Analyzed	0 participants	23 participants	21 participants	0 participants	0 participants
			12.12; (6.83 to 29.54)	14.06; (4.37 to 30.59)
SCCHN I-O naive	Number Analyzed	0 participants	0 participants	0 participants	0 participants	6 participants
						4.21 [1]; (1.68 to NA)
Cervical, Randomized	Number Analyzed	19 participants	45 participants	45 participants	0 participants	0 participants
		21.55; (8.25 to 44.85)	17.12; (10.22 to 34.79)	22.74; (14.62 to 32.82)
Cervical, Pooled	Number Analyzed	0 participants	0 participants	112 participants	0 participants	0 participants
				20.93; (14.39 to 29.04)
Vaginal/Vulvar	Number Analyzed	5 participants	0 participants	0 participants	0 participants	0 participants
		10.28; (3.88 to 23.72)
MCC	Number Analyzed	25 participants	43 participants	0 participants	0 participants	0 participants
		80.66 [1]; (23.26 to NA)	29.83; (8.51 to 48.33)
NPC	Number Analyzed	24 participants	42 participants	0 participants	0 participants	0 participants
		22.74; (12.62 to 35.29)	23.66; (16.82 to 41.43)

[1]

Upper limit not calculable as upper CI bound does not cross 50% threshold

7. Secondary Outcome

Title	Metastatic: Investigator-Assessed Progression-Free Survival (PFS)
Description	Investigator-assessed progression free survival (PFS) is defined as the time from first dosing date to the date of the first documented tumor progression, as determined by investigators (per RECIST 1.1), or death due to any cause, whichever occurs first. Participants with the following diseases will be assessed: EBV positive related gastric cancer;; HPV positive SCCHN;; Other anogenital HPV associated cancers;; GYN (Cervical, Vaginal, Vulvar) carcinoma;; Merkel cell carcinoma (MCC);; Nasopharyngeal carcinoma (NPC) Note: "Cervical, Randomized" and "Cervical, Pooled" are not mutually exclusive categories
Time Frame	From the first dosing date to the date of the first documented tumor progression or death due to any cause, whichever occurs first (Up to 83 months)

Outcome Measure Data

Analysis Population Description

All treated participants in the metastatic cohorts

Arm/Group Title		Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D
Arm/Group Description:		Nivolumab IV over 30 minutes at 240 mg every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks + Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 1 mg/kg IV over 30 minutes + Ipilimumab 3 mg/kg IV over 30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 240 mg IV over 30 minutes + BMS-986016 (Relatlimab) 80 mg IV over 60 minutes administered every 2 weeks for a maximum of 24 months, or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Daratumumab 16 mg/kg IV weekly for the first 8 weeks. Starting at Week 3, Nivolumab 240 mg IV over 30 minutes every 2 weeks. Daratumumab 16 mg/kg every 2 weeks from Weeks 9-24. Starting at Week 25, Nivolumab 480 mg IV flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of consent, whichever comes first
Overall Number of Participants Analyzed		113	195	133	8	6
Median (95% Confidence Interval); Unit of Measure: Months
EBV positive related gastric cancer	Number Analyzed	14 participants	0 participants	0 participants	0 participants	0 participants
		2.94; (1.05 to 3.75)
HPV positive SCCHN	Number Analyzed	26 participants	42 participants	0 participants	8 participants	0 participants
		3.25; (1.84 to 6.93)	3.71; (1.77 to 6.80)		3.81; (1.77 to 7.39)
Other anogenital HPV associated cancers	Number Analyzed	0 participants	23 participants	21 participants	0 participants	0 participants
			4.63; (1.94 to 14.29)	3.58; (2.04 to 7.49)
SCCHN I-O naive	Number Analyzed	0 participants	0 participants	0 participants	0 participants	6 participants
						1.81 [1]; (1.08 to NA)
Cervical, Randomized	Number Analyzed	19 participants	45 participants	45 participants	0 participants	0 participants
		5.09; (1.87 to 9.07)	3.75; (3.32 to 9.23)	7.11; (3.71 to 17.25)
Cervical, Pooled	Number Analyzed	0 participants	0 participants	112 participants	0 participants	0 participants
				5.85; (3.75 to 9.03)
Vaginal/Vulvar	Number Analyzed	5 participants	0 participants	0 participants	0 participants	0 participants
		3.75; (1.22 to 8.15)
MCC	Number Analyzed	25 participants	43 participants	0 participants	0 participants	0 participants
		21.32; (9.20 to 62.52)	8.39; (3.71 to 24.34)
NPC	Number Analyzed	24 participants	42 participants	0 participants	0 participants	0 participants
		1.94; (1.54 to 3.58)	5.36; (2.37 to 9.23)

[1]

Upper limit not calculable as upper CI bound does not cross 50% threshold

8. Post-Hoc Outcome

Title	Metastatic: Investigator-Assessed Objective Response Rate (ORR) Extended Collection
Description	ORR is defined as the percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) using RECIST 1.1 criteria. An ORR in excess of 10% will be considered of clinical interest, and an ORR of 25% or greater will be considered of strong clinical interest. 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. Participants with the following diseases will be assessed: EBV positive related gastric cancer;; HPV positive SCCHN;; Other anogenital HPV associated cancers;; GYN (Cervical, Vaginal, Vulvar) carcinoma;; Merkel cell carcinoma (MCC);; Nasopharyngeal carcinoma (NPC) Note: "Cervical, Randomized" and "Cervical, Pooled" are not mutually exclusive categories
Time Frame	From the date of first dose to the date of the initial objectively documented tumor progression or the date of the last tumor assessment prior to subsequent therapy (Up to 83 months)

Outcome Measure Data

Analysis Population Description

All treated participants in the metastatic cohorts

Arm/Group Title		Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D
Arm/Group Description:		Nivolumab IV over 30 minutes at 240 mg every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks + Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 1 mg/kg IV over 30 minutes + Ipilimumab 3 mg/kg IV over 30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 240 mg IV over 30 minutes + BMS-986016 (Relatlimab) 80 mg IV over 60 minutes administered every 2 weeks for a maximum of 24 months, or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Daratumumab 16 mg/kg IV weekly for the first 8 weeks. Starting at Week 3, Nivolumab 240 mg IV over 30 minutes every 2 weeks. Daratumumab 16 mg/kg every 2 weeks from Weeks 9-24. Starting at Week 25, Nivolumab 480 mg IV flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of consent, whichever comes first
Overall Number of Participants Analyzed		113	195	133	8	6
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
EBV positive related gastric cancer	Number Analyzed	14 participants	0 participants	0 participants	0 participants	0 participants
		14.3; (1.8 to 42.8)
HPV positive SCCHN	Number Analyzed	26 participants	42 participants	0 participants	8 participants	0 participants
		11.5; (2.4 to 30.2)	31.0; (17.6 to 47.1)		0; (0.0 to 36.9)
Other anogenital HPV associated cancers	Number Analyzed	0 participants	23 participants	21 participants	0 participants	0 participants
			34.8; (16.4 to 57.3)	23.8; (8.2 to 47.2)
SCCHN I-O naive	Number Analyzed	0 participants	0 participants	0 participants	0 participants	6 participants
						16.7; (0.4 to 64.1)
Cervical, Randomized	Number Analyzed	19 participants	45 participants	45 participants	0 participants	0 participants
		26.3; (9.1 to 51.2)	31.1; (18.2 to 46.6)	40.0; (25.7 to 55.7)
Cervical, Pooled	Number Analyzed	0 participants	0 participants	112 participants	0 participants	0 participants
				40.2; (31.0 to 49.9)
Vaginal/Vulvar	Number Analyzed	5 participants	0 participants	0 participants	0 participants	0 participants
		20.0; (0.5 to 71.6)
MCC	Number Analyzed	25 participants	43 participants	0 participants	0 participants	0 participants
		60.0; (38.7 to 78.9)	58.1; (42.1 to 73.0)
NPC	Number Analyzed	24 participants	42 participants	0 participants	0 participants	0 participants
		16.7; (4.7 to 37.4)	28.6; (15.7 to 44.6)

Adverse Events

Time Frame	SAEs and Other AEs are assessed from first dose to 100 days post last dose (Up to 83 months) Participants were assessed for all-cause mortality from their first dose to their study completion (Up to 84 months)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D	Neoadjuvant
Arm/Group Description	Nivolumab IV over 30 minutes at 240 mg every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks + Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 1 mg/kg IV over 30 minutes + Ipilimumab 3 mg/kg IV over 30 minutes every 3 weeks for 4 doses followed by Nivolumab 240 mg IV over 30 minutes every 2 weeks for a maximum of 24 months or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab 240 mg IV over 30 minutes + BMS-986016 (Relatlimab) 80 mg IV over 60 minutes administered every 2 weeks for a maximum of 24 months, or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Daratumumab 16 mg/kg IV weekly for the first 8 weeks. Starting at Week 3, Nivolumab 240 mg IV over 30 minutes every 2 weeks. Daratumumab 16 mg/kg every 2 weeks from Weeks 9-24. Starting at Week 25, Nivolumab 480 mg IV flat dose over 30 minutes every 4 weeks; daratumumab 16 mg/kg every 4 weeks for a maximum of 24 months or until progression, unacceptable toxicity, or withdrawal of consent, whichever comes first	Nivolumab IV over 30 minutes at 240 mg for 2 doses, on Day 1 and Day 15
All-Cause Mortality
	Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D	Neoadjuvant
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	82/113 (72.57%)	133/195 (68.21%)	86/133 (64.66%)	7/8 (87.50%)	5/6 (83.33%)	40/123 (32.52%)
Serious Adverse Events
	Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D	Neoadjuvant
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	59/113 (52.21%)	130/195 (66.67%)	99/133 (74.44%)	5/8 (62.50%)	5/6 (83.33%)	40/123 (32.52%)
Blood and lymphatic system disorders
Anaemia † 1	1/113 (0.88%)	1/195 (0.51%)	5/133 (3.76%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Febrile neutropenia † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	2/123 (1.63%)
Iron deficiency anaemia † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Lymph node pain † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Acute myocardial infarction † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Angina pectoris † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Atrial fibrillation † 1	1/113 (0.88%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Autoimmune pericarditis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cardiac arrest † 1	0/113 (0.00%)	0/195 (0.00%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cardiac failure † 1	2/113 (1.77%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cardiac tamponade † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Coronary artery disease † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Mitral valve incompetence † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Myocardial infarction † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Myocarditis † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pericardial effusion † 1	0/113 (0.00%)	2/195 (1.03%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Sinus bradycardia † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Supraventricular tachycardia † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Endocrine disorders
Adrenal insufficiency † 1	1/113 (0.88%)	4/195 (2.05%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Glucocorticoid deficiency † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hyperthyroidism † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hypophysitis † 1	0/113 (0.00%)	0/195 (0.00%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hypothyroidism † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Inappropriate antidiuretic hormone secretion † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Thyroid disorder † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Eye disorders
Uveitis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Gastrointestinal disorders
Abdominal distension † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Abdominal pain † 1	0/113 (0.00%)	3/195 (1.54%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Abdominal pain lower † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Anal fistula † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Anorectal disorder † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Ascites † 1	1/113 (0.88%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Colitis † 1	1/113 (0.88%)	3/195 (1.54%)	11/133 (8.27%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Constipation † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Diarrhoea † 1	1/113 (0.88%)	9/195 (4.62%)	4/133 (3.01%)	0/8 (0.00%)	0/6 (0.00%)	2/123 (1.63%)
Dysphagia † 1	1/113 (0.88%)	3/195 (1.54%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Gastritis † 1	0/113 (0.00%)	1/195 (0.51%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Gastrointestinal haemorrhage † 1	1/113 (0.88%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Gastrointestinal motility disorder † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Glossodynia † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Ileus † 1	0/113 (0.00%)	0/195 (0.00%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Immune-mediated enterocolitis † 1	1/113 (0.88%)	1/195 (0.51%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Immune-mediated pancreatitis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Intestinal obstruction † 1	1/113 (0.88%)	0/195 (0.00%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Intestinal perforation † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Large intestinal obstruction † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Mouth haemorrhage † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	3/123 (2.44%)
Nausea † 1	0/113 (0.00%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Oesophageal motility disorder † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Oesophagitis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pancreatitis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Proctalgia † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Small intestinal obstruction † 1	2/113 (1.77%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Stomatitis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Vomiting † 1	0/113 (0.00%)	4/195 (2.05%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
General disorders
Asthenia † 1	1/113 (0.88%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Chills † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Complication associated with device † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Death † 1	1/113 (0.88%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Disease progression † 1	1/113 (0.88%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Facial pain † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Fatigue † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
General physical health deterioration † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hyperthermia † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Malaise † 1	2/113 (1.77%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Mucosal inflammation † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	3/123 (2.44%)
Multiple organ dysfunction syndrome † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Non-cardiac chest pain † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Oedema peripheral † 1	0/113 (0.00%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pain † 1	1/113 (0.88%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Performance status decreased † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pyrexia † 1	3/113 (2.65%)	5/195 (2.56%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	2/123 (1.63%)
Sudden death † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Systemic inflammatory response syndrome † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Hepatobiliary disorders
Autoimmune cholangitis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Autoimmune hepatitis † 1	0/113 (0.00%)	1/195 (0.51%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Bile duct stenosis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Biliary obstruction † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Biliary tract disorder † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cholecystitis † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Gallbladder rupture † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hepatic cytolysis † 1	2/113 (1.77%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hepatic function abnormal † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hepatitis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hepatitis toxic † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hepatotoxicity † 1	0/113 (0.00%)	0/195 (0.00%)	6/133 (4.51%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hypertransaminasaemia † 1	0/113 (0.00%)	0/195 (0.00%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Immune system disorders
Anaphylactic reaction † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hypersensitivity † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Sarcoidosis † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Infections and infestations
Abscess neck † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Arthritis bacterial † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Bacteraemia † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
COVID-19 † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Catheter site infection † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cellulitis † 1	1/113 (0.88%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Clostridial sepsis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Clostridium difficile colitis † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Device related infection † 1	2/113 (1.77%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Device related sepsis † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Encephalitis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Gastroenteritis † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Gastroenteritis bacterial † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Kidney infection † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Large intestine infection † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Localised infection † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Lower respiratory tract infection † 1	0/113 (0.00%)	3/195 (1.54%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Medical device site infection † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Meningitis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Meningitis aseptic † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Osteomyelitis † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Otitis media † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Periorbital infection † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pneumonia † 1	2/113 (1.77%)	3/195 (1.54%)	1/133 (0.75%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Pneumonia aspiration † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Pneumonia bacterial † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Post procedural infection † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Postoperative wound infection † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Pulmonary sepsis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pyelonephritis † 1	1/113 (0.88%)	1/195 (0.51%)	4/133 (3.01%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pyelonephritis acute † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Respiratory tract infection † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Sepsis † 1	3/113 (2.65%)	6/195 (3.08%)	4/133 (3.01%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Septic shock † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Sinusitis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Skin infection † 1	0/113 (0.00%)	1/195 (0.51%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Soft tissue infection † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Tuberculosis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Upper respiratory tract infection † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Urinary tract infection † 1	3/113 (2.65%)	11/195 (5.64%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Urosepsis † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Vascular device infection † 1	1/113 (0.88%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Injury, poisoning and procedural complications
Fracture † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hip fracture † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Post procedural fistula † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Post procedural haemorrhage † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Postoperative wound complication † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Procedural pain † 1	0/113 (0.00%)	0/195 (0.00%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Recall phenomenon † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Spinal compression fracture † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Subdural haematoma † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Transfusion reaction † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Investigations
Alanine aminotransferase increased † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Aspartate aminotransferase increased † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Blood bilirubin increased † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Blood creatinine increased † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Blood magnesium decreased † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Blood pressure decreased † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cytomegalovirus test positive † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
General physical condition abnormal † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
International normalised ratio increased † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Lipase increased † 1	0/113 (0.00%)	2/195 (1.03%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Liver function test increased † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Respiratory syncytial virus test positive † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Troponin I increased † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Troponin increased † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Urine output decreased † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Dehydration † 1	1/113 (0.88%)	4/195 (2.05%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	3/123 (2.44%)
Diabetic ketoacidosis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hypercalcaemia † 1	1/113 (0.88%)	4/195 (2.05%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Hyperglycaemia † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hyperkalaemia † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hypokalaemia † 1	0/113 (0.00%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hyponatraemia † 1	0/113 (0.00%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hypophagia † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Type 1 diabetes mellitus † 1	0/113 (0.00%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/113 (0.00%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Back pain † 1	1/113 (0.88%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Fistula † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Flank pain † 1	0/113 (0.00%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Intervertebral disc protrusion † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Muscular weakness † 1	0/113 (0.00%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Myositis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pain in extremity † 1	0/113 (0.00%)	4/195 (2.05%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pathological fracture † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Extranodal marginal zone B-cell lymphoma (MALT type) † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Infected neoplasm † 1	0/113 (0.00%)	1/195 (0.51%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Lung adenocarcinoma † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Lung neoplasm malignant † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Malignant melanoma † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Malignant neoplasm progression † 1	24/113 (21.24%)	39/195 (20.00%)	21/133 (15.79%)	2/8 (25.00%)	3/6 (50.00%)	2/123 (1.63%)
Metastases to central nervous system † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Metastasis † 1	2/113 (1.77%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Neuroendocrine carcinoma of the skin † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Prostate cancer † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Squamous cell carcinoma of skin † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Transitional cell carcinoma † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Tumour haemorrhage † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Tumour obstruction † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Tumour pain † 1	1/113 (0.88%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Nervous system disorders
Basal ganglia infarction † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Bell's palsy † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Carotid artery aneurysm † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cerebral haemorrhage † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cerebral infarction † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cerebral ischaemia † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Cerebrovascular accident † 1	1/113 (0.88%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Depressed level of consciousness † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Dizziness † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Embolic stroke † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Encephalopathy † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Guillain-Barre syndrome † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Haemorrhage intracranial † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Headache † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Intraventricular haemorrhage † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Monoparesis † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Myasthenia gravis † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Peripheral motor neuropathy † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Peripheral sensory neuropathy † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Seizure † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Spinal cord compression † 1	0/113 (0.00%)	3/195 (1.54%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Syncope † 1	1/113 (0.88%)	3/195 (1.54%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Product Issues
Device occlusion † 1	1/113 (0.88%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Psychiatric disorders
Confusional state † 1	0/113 (0.00%)	3/195 (1.54%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Mental status changes † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	2/113 (1.77%)	5/195 (2.56%)	8/133 (6.02%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Autoimmune nephritis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Haematuria † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Hydronephrosis † 1	0/113 (0.00%)	2/195 (1.03%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Oliguria † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Renal colic † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Renal failure † 1	0/113 (0.00%)	3/195 (1.54%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Renal haematoma † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Ureteric stenosis † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Urinary incontinence † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Urinary retention † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Urinary tract obstruction † 1	0/113 (0.00%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Urogenital fistula † 1	1/113 (0.88%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Reproductive system and breast disorders
Female genital tract fistula † 1	0/113 (0.00%)	1/195 (0.51%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pelvic pain † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Prostatic obstruction † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Vaginal haemorrhage † 1	0/113 (0.00%)	0/195 (0.00%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Vulval disorder † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Aspiration † 1	0/113 (0.00%)	3/195 (1.54%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	2/123 (1.63%)
Asthma † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Dyspnoea † 1	4/113 (3.54%)	2/195 (1.03%)	0/133 (0.00%)	2/8 (25.00%)	0/6 (0.00%)	0/123 (0.00%)
Haemoptysis † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Hypoxia † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Immune-mediated lung disease † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Laryngeal oedema † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Lung disorder † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pleural effusion † 1	1/113 (0.88%)	3/195 (1.54%)	1/133 (0.75%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Pneumonitis † 1	4/113 (3.54%)	7/195 (3.59%)	10/133 (7.52%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pneumothorax † 1	1/113 (0.88%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Productive cough † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Pulmonary embolism † 1	1/113 (0.88%)	2/195 (1.03%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Pulmonary haemorrhage † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Stridor † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Skin and subcutaneous tissue disorders
Hyperhidrosis † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Rash † 1	0/113 (0.00%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Rash maculo-papular † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Rash pruritic † 1	0/113 (0.00%)	0/195 (0.00%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Surgical and medical procedures
Debridement † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Vascular disorders
Arterial haemorrhage † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Deep vein thrombosis † 1	0/113 (0.00%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Embolism † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Haematoma † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Hypotension † 1	2/113 (1.77%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Iliac vein stenosis † 1	0/113 (0.00%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Lymphoedema † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Orthostatic hypotension † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
1 Term from vocabulary, 25.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Metastatic Monotherapy	Metastatic Combo A	Metastatic Combo B	Metastatic Combo C	Metastatic Combo D	Neoadjuvant
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	110/113 (97.35%)	189/195 (96.92%)	129/133 (96.99%)	7/8 (87.50%)	5/6 (83.33%)	108/123 (87.80%)
Blood and lymphatic system disorders
Anaemia † 1	28/113 (24.78%)	53/195 (27.18%)	42/133 (31.58%)	2/8 (25.00%)	2/6 (33.33%)	11/123 (8.94%)
Ear and labyrinth disorders
Ear pain † 1	3/113 (2.65%)	4/195 (2.05%)	1/133 (0.75%)	0/8 (0.00%)	1/6 (16.67%)	2/123 (1.63%)
Vertigo † 1	6/113 (5.31%)	1/195 (0.51%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Endocrine disorders
Hyperthyroidism † 1	2/113 (1.77%)	9/195 (4.62%)	21/133 (15.79%)	0/8 (0.00%)	0/6 (0.00%)	4/123 (3.25%)
Hypothyroidism † 1	17/113 (15.04%)	39/195 (20.00%)	31/133 (23.31%)	2/8 (25.00%)	1/6 (16.67%)	3/123 (2.44%)
Gastrointestinal disorders
Abdominal pain † 1	18/113 (15.93%)	28/195 (14.36%)	30/133 (22.56%)	1/8 (12.50%)	0/6 (0.00%)	8/123 (6.50%)
Abdominal pain upper † 1	12/113 (10.62%)	9/195 (4.62%)	5/133 (3.76%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Colitis † 1	2/113 (1.77%)	6/195 (3.08%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	4/123 (3.25%)
Constipation † 1	27/113 (23.89%)	51/195 (26.15%)	37/133 (27.82%)	1/8 (12.50%)	0/6 (0.00%)	21/123 (17.07%)
Diarrhoea † 1	31/113 (27.43%)	61/195 (31.28%)	54/133 (40.60%)	1/8 (12.50%)	2/6 (33.33%)	22/123 (17.89%)
Dry mouth † 1	8/113 (7.08%)	13/195 (6.67%)	6/133 (4.51%)	1/8 (12.50%)	0/6 (0.00%)	6/123 (4.88%)
Dyspepsia † 1	4/113 (3.54%)	11/195 (5.64%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Dysphagia † 1	10/113 (8.85%)	12/195 (6.15%)	2/133 (1.50%)	4/8 (50.00%)	0/6 (0.00%)	21/123 (17.07%)
Nausea † 1	25/113 (22.12%)	45/195 (23.08%)	48/133 (36.09%)	2/8 (25.00%)	3/6 (50.00%)	42/123 (34.15%)
Stomatitis † 1	7/113 (6.19%)	5/195 (2.56%)	4/133 (3.01%)	0/8 (0.00%)	0/6 (0.00%)	5/123 (4.07%)
Tongue ulceration † 1	0/113 (0.00%)	1/195 (0.51%)	1/133 (0.75%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Vomiting † 1	21/113 (18.58%)	31/195 (15.90%)	33/133 (24.81%)	1/8 (12.50%)	0/6 (0.00%)	14/123 (11.38%)
General disorders
Asthenia † 1	18/113 (15.93%)	26/195 (13.33%)	23/133 (17.29%)	0/8 (0.00%)	0/6 (0.00%)	11/123 (8.94%)
Chest pain † 1	6/113 (5.31%)	2/195 (1.03%)	1/133 (0.75%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Chills † 1	6/113 (5.31%)	10/195 (5.13%)	9/133 (6.77%)	0/8 (0.00%)	0/6 (0.00%)	3/123 (2.44%)
Face oedema † 1	2/113 (1.77%)	6/195 (3.08%)	1/133 (0.75%)	0/8 (0.00%)	1/6 (16.67%)	3/123 (2.44%)
Facial pain † 1	3/113 (2.65%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	3/123 (2.44%)
Fatigue † 1	47/113 (41.59%)	81/195 (41.54%)	46/133 (34.59%)	6/8 (75.00%)	1/6 (16.67%)	40/123 (32.52%)
Gait disturbance † 1	0/113 (0.00%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Inflammation † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Influenza like illness † 1	4/113 (3.54%)	12/195 (6.15%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	3/123 (2.44%)
Localised oedema † 1	0/113 (0.00%)	2/195 (1.03%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	8/123 (6.50%)
Malaise † 1	4/113 (3.54%)	3/195 (1.54%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Mucosal inflammation † 1	4/113 (3.54%)	6/195 (3.08%)	5/133 (3.76%)	0/8 (0.00%)	0/6 (0.00%)	15/123 (12.20%)
Non-cardiac chest pain † 1	5/113 (4.42%)	3/195 (1.54%)	3/133 (2.26%)	1/8 (12.50%)	0/6 (0.00%)	2/123 (1.63%)
Oedema peripheral † 1	16/113 (14.16%)	21/195 (10.77%)	20/133 (15.04%)	1/8 (12.50%)	2/6 (33.33%)	6/123 (4.88%)
Pain † 1	3/113 (2.65%)	9/195 (4.62%)	4/133 (3.01%)	1/8 (12.50%)	1/6 (16.67%)	2/123 (1.63%)
Pyrexia † 1	14/113 (12.39%)	34/195 (17.44%)	33/133 (24.81%)	0/8 (0.00%)	2/6 (33.33%)	13/123 (10.57%)
Infections and infestations
Bronchitis † 1	8/113 (7.08%)	3/195 (1.54%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Candida infection † 1	3/113 (2.65%)	5/195 (2.56%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	3/123 (2.44%)
Conjunctivitis † 1	6/113 (5.31%)	4/195 (2.05%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Eye infection † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Mucosal infection † 1	2/113 (1.77%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	1/123 (0.81%)
Nasopharyngitis † 1	10/113 (8.85%)	14/195 (7.18%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Oral bacterial infection † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Otitis externa † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Respiratory tract infection † 1	3/113 (2.65%)	7/195 (3.59%)	2/133 (1.50%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Rhinitis † 1	6/113 (5.31%)	4/195 (2.05%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Tracheitis † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Upper respiratory tract infection † 1	7/113 (6.19%)	27/195 (13.85%)	8/133 (6.02%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Urinary tract infection † 1	9/113 (7.96%)	21/195 (10.77%)	31/133 (23.31%)	0/8 (0.00%)	0/6 (0.00%)	9/123 (7.32%)
Injury, poisoning and procedural complications
Fall † 1	0/113 (0.00%)	1/195 (0.51%)	2/133 (1.50%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Fracture † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Infusion related reaction † 1	5/113 (4.42%)	11/195 (5.64%)	4/133 (3.01%)	0/8 (0.00%)	0/6 (0.00%)	4/123 (3.25%)
Jaw fracture † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Procedural pain † 1	3/113 (2.65%)	3/195 (1.54%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	9/123 (7.32%)
Radiation skin injury † 1	1/113 (0.88%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	15/123 (12.20%)
Investigations
Alanine aminotransferase increased † 1	8/113 (7.08%)	26/195 (13.33%)	22/133 (16.54%)	0/8 (0.00%)	0/6 (0.00%)	4/123 (3.25%)
Amylase increased † 1	6/113 (5.31%)	20/195 (10.26%)	12/133 (9.02%)	1/8 (12.50%)	0/6 (0.00%)	7/123 (5.69%)
Aspartate aminotransferase increased † 1	10/113 (8.85%)	25/195 (12.82%)	20/133 (15.04%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Blood alkaline phosphatase increased † 1	5/113 (4.42%)	10/195 (5.13%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	3/123 (2.44%)
Blood creatinine increased † 1	11/113 (9.73%)	19/195 (9.74%)	13/133 (9.77%)	0/8 (0.00%)	0/6 (0.00%)	4/123 (3.25%)
Breath sounds abnormal † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	1/123 (0.81%)
Lipase increased † 1	17/113 (15.04%)	27/195 (13.85%)	17/133 (12.78%)	2/8 (25.00%)	0/6 (0.00%)	7/123 (5.69%)
Lymphocyte count decreased † 1	1/113 (0.88%)	16/195 (8.21%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	2/123 (1.63%)
Platelet count decreased † 1	0/113 (0.00%)	11/195 (5.64%)	0/133 (0.00%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Troponin increased † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Weight decreased † 1	10/113 (8.85%)	24/195 (12.31%)	8/133 (6.02%)	2/8 (25.00%)	0/6 (0.00%)	15/123 (12.20%)
White blood cell count decreased † 1	2/113 (1.77%)	10/195 (5.13%)	4/133 (3.01%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Metabolism and nutrition disorders
Decreased appetite † 1	24/113 (21.24%)	48/195 (24.62%)	32/133 (24.06%)	2/8 (25.00%)	1/6 (16.67%)	15/123 (12.20%)
Dehydration † 1	1/113 (0.88%)	9/195 (4.62%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	8/123 (6.50%)
Hypercalcaemia † 1	3/113 (2.65%)	9/195 (4.62%)	4/133 (3.01%)	0/8 (0.00%)	1/6 (16.67%)	2/123 (1.63%)
Hyperglycaemia † 1	3/113 (2.65%)	16/195 (8.21%)	9/133 (6.77%)	0/8 (0.00%)	0/6 (0.00%)	3/123 (2.44%)
Hypoalbuminaemia † 1	2/113 (1.77%)	14/195 (7.18%)	16/133 (12.03%)	0/8 (0.00%)	0/6 (0.00%)	2/123 (1.63%)
Hypokalaemia † 1	6/113 (5.31%)	20/195 (10.26%)	15/133 (11.28%)	1/8 (12.50%)	0/6 (0.00%)	11/123 (8.94%)
Hypomagnesaemia † 1	10/113 (8.85%)	14/195 (7.18%)	17/133 (12.78%)	1/8 (12.50%)	0/6 (0.00%)	10/123 (8.13%)
Hyponatraemia † 1	4/113 (3.54%)	24/195 (12.31%)	14/133 (10.53%)	1/8 (12.50%)	1/6 (16.67%)	9/123 (7.32%)
Hypophosphataemia † 1	5/113 (4.42%)	20/195 (10.26%)	3/133 (2.26%)	1/8 (12.50%)	0/6 (0.00%)	4/123 (3.25%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	24/113 (21.24%)	35/195 (17.95%)	26/133 (19.55%)	2/8 (25.00%)	1/6 (16.67%)	10/123 (8.13%)
Back pain † 1	17/113 (15.04%)	28/195 (14.36%)	19/133 (14.29%)	1/8 (12.50%)	1/6 (16.67%)	4/123 (3.25%)
Flank pain † 1	6/113 (5.31%)	7/195 (3.59%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Groin pain † 1	2/113 (1.77%)	3/195 (1.54%)	2/133 (1.50%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Muscular weakness † 1	2/113 (1.77%)	10/195 (5.13%)	4/133 (3.01%)	1/8 (12.50%)	0/6 (0.00%)	4/123 (3.25%)
Musculoskeletal chest pain † 1	8/113 (7.08%)	11/195 (5.64%)	2/133 (1.50%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Musculoskeletal pain † 1	4/113 (3.54%)	5/195 (2.56%)	2/133 (1.50%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Myalgia † 1	10/113 (8.85%)	19/195 (9.74%)	10/133 (7.52%)	0/8 (0.00%)	0/6 (0.00%)	6/123 (4.88%)
Neck pain † 1	3/113 (2.65%)	7/195 (3.59%)	1/133 (0.75%)	1/8 (12.50%)	0/6 (0.00%)	6/123 (4.88%)
Pain in extremity † 1	12/113 (10.62%)	13/195 (6.67%)	9/133 (6.77%)	0/8 (0.00%)	0/6 (0.00%)	4/123 (3.25%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin † 1	3/113 (2.65%)	1/195 (0.51%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Tumour pain † 1	7/113 (6.19%)	5/195 (2.56%)	3/133 (2.26%)	1/8 (12.50%)	0/6 (0.00%)	1/123 (0.81%)
Nervous system disorders
Dizziness † 1	12/113 (10.62%)	19/195 (9.74%)	15/133 (11.28%)	0/8 (0.00%)	0/6 (0.00%)	6/123 (4.88%)
Dysgeusia † 1	7/113 (6.19%)	3/195 (1.54%)	3/133 (2.26%)	0/8 (0.00%)	0/6 (0.00%)	10/123 (8.13%)
Headache † 1	13/113 (11.50%)	31/195 (15.90%)	22/133 (16.54%)	0/8 (0.00%)	2/6 (33.33%)	6/123 (4.88%)
Paraesthesia † 1	2/113 (1.77%)	3/195 (1.54%)	2/133 (1.50%)	2/8 (25.00%)	0/6 (0.00%)	3/123 (2.44%)
Peripheral sensory neuropathy † 1	2/113 (1.77%)	4/195 (2.05%)	4/133 (3.01%)	0/8 (0.00%)	1/6 (16.67%)	8/123 (6.50%)
Psychiatric disorders
Anxiety † 1	10/113 (8.85%)	8/195 (4.10%)	4/133 (3.01%)	1/8 (12.50%)	0/6 (0.00%)	9/123 (7.32%)
Confusional state † 1	1/113 (0.88%)	5/195 (2.56%)	2/133 (1.50%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
Insomnia † 1	10/113 (8.85%)	23/195 (11.79%)	8/133 (6.02%)	1/8 (12.50%)	1/6 (16.67%)	2/123 (1.63%)
Reproductive system and breast disorders
Pelvic pain † 1	2/113 (1.77%)	6/195 (3.08%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Vaginal haemorrhage † 1	1/113 (0.88%)	6/195 (3.08%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	4/123 (3.25%)
Respiratory, thoracic and mediastinal disorders
Aspiration † 1	0/113 (0.00%)	4/195 (2.05%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	3/123 (2.44%)
Cough † 1	26/113 (23.01%)	49/195 (25.13%)	17/133 (12.78%)	2/8 (25.00%)	1/6 (16.67%)	7/123 (5.69%)
Dyspnoea † 1	21/113 (18.58%)	30/195 (15.38%)	13/133 (9.77%)	2/8 (25.00%)	1/6 (16.67%)	3/123 (2.44%)
Dyspnoea exertional † 1	7/113 (6.19%)	4/195 (2.05%)	1/133 (0.75%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Laryngeal inflammation † 1	0/113 (0.00%)	0/195 (0.00%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	1/123 (0.81%)
Nasal congestion † 1	5/113 (4.42%)	11/195 (5.64%)	4/133 (3.01%)	0/8 (0.00%)	0/6 (0.00%)	1/123 (0.81%)
Oropharyngeal pain † 1	6/113 (5.31%)	10/195 (5.13%)	3/133 (2.26%)	0/8 (0.00%)	1/6 (16.67%)	6/123 (4.88%)
Pleural effusion † 1	4/113 (3.54%)	4/195 (2.05%)	1/133 (0.75%)	1/8 (12.50%)	0/6 (0.00%)	0/123 (0.00%)
Pneumonitis † 1	8/113 (7.08%)	9/195 (4.62%)	9/133 (6.77%)	0/8 (0.00%)	0/6 (0.00%)	0/123 (0.00%)
Productive cough † 1	3/113 (2.65%)	7/195 (3.59%)	7/133 (5.26%)	0/8 (0.00%)	0/6 (0.00%)	3/123 (2.44%)
Upper-airway cough syndrome † 1	0/113 (0.00%)	6/195 (3.08%)	1/133 (0.75%)	1/8 (12.50%)	0/6 (0.00%)	1/123 (0.81%)
Skin and subcutaneous tissue disorders
Dry skin † 1	10/113 (8.85%)	14/195 (7.18%)	12/133 (9.02%)	0/8 (0.00%)	1/6 (16.67%)	3/123 (2.44%)
Night sweats † 1	1/113 (0.88%)	3/195 (1.54%)	1/133 (0.75%)	1/8 (12.50%)	0/6 (0.00%)	1/123 (0.81%)
Pruritus † 1	23/113 (20.35%)	60/195 (30.77%)	35/133 (26.32%)	0/8 (0.00%)	1/6 (16.67%)	11/123 (8.94%)
Rash † 1	17/113 (15.04%)	49/195 (25.13%)	16/133 (12.03%)	1/8 (12.50%)	0/6 (0.00%)	7/123 (5.69%)
Rash maculo-papular † 1	8/113 (7.08%)	20/195 (10.26%)	25/133 (18.80%)	0/8 (0.00%)	0/6 (0.00%)	6/123 (4.88%)
Skin ulcer † 1	0/113 (0.00%)	2/195 (1.03%)	1/133 (0.75%)	0/8 (0.00%)	2/6 (33.33%)	0/123 (0.00%)
Vascular disorders
Haematoma † 1	2/113 (1.77%)	2/195 (1.03%)	0/133 (0.00%)	1/8 (12.50%)	0/6 (0.00%)	2/123 (1.63%)
Hypertension † 1	10/113 (8.85%)	7/195 (3.59%)	5/133 (3.76%)	1/8 (12.50%)	0/6 (0.00%)	12/123 (9.76%)
Hypotension † 1	5/113 (4.42%)	10/195 (5.13%)	4/133 (3.01%)	0/8 (0.00%)	1/6 (16.67%)	4/123 (3.25%)
Lymphoedema † 1	4/113 (3.54%)	4/195 (2.05%)	5/133 (3.76%)	1/8 (12.50%)	1/6 (16.67%)	2/123 (1.63%)
Venous thrombosis † 1	1/113 (0.88%)	0/195 (0.00%)	0/133 (0.00%)	0/8 (0.00%)	1/6 (16.67%)	0/123 (0.00%)
1 Term from vocabulary, 25.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

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

Results Point of Contact

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

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

Ferris RL, Spanos WC, Leidner R, Goncalves A, Martens UM, Kyi C, Sharfman W, Chung CH, Devriese LA, Gauthier H, Chiosea SI, Vujanovic L, Taube JM, Stein JE, Li J, Li B, Chen T, Barrows A, Topalian SL. Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial. J Immunother Cancer. 2021 Jun;9(6):e002568. doi: 10.1136/jitc-2021-002568. Erratum In: J Immunother Cancer. 2021 Aug;9(8):

Topalian SL, Bhatia S, Amin A, Kudchadkar RR, Sharfman WH, Lebbe C, Delord JP, Dunn LA, Shinohara MM, Kulikauskas R, Chung CH, Martens UM, Ferris RL, Stein JE, Engle EL, Devriese LA, Lao CD, Gu J, Li B, Chen T, Barrows A, Horvath A, Taube JM, Nghiem P. Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial. J Clin Oncol. 2020 Aug 1;38(22):2476-2487. doi: 10.1200/JCO.20.00201. Epub 2020 Apr 23.

Naumann RW, Hollebecque A, Meyer T, Devlin MJ, Oaknin A, Kerger J, Lopez-Picazo JM, Machiels JP, Delord JP, Evans TRJ, Boni V, Calvo E, Topalian SL, Chen T, Soumaoro I, Li B, Gu J, Zwirtes R, Moore KN. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol. 2019 Nov 1;37(31):2825-2834. doi: 10.1200/JCO.19.00739. Epub 2019 Sep 5.

Appelbaum J, Wells D, Hiatt JB, Steinbach G, Stewart FM, Thomas H, Nghiem P, Kapur RP, Thompson JA, Bhatia S. Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report. J Immunother Cancer. 2018 Aug 31;6(1):82. doi: 10.1186/s40425-018-0396-9.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02488759
• Other Study ID Numbers: CA209-358; 2015-000230-29 ( EudraCT Number )
• First Submitted: June 30, 2015
• First Posted: July 2, 2015
• Results First Submitted: March 17, 2022
• Results First Posted: April 12, 2022
• Last Update Posted: November 13, 2023