Trial of Nivolumab vs Therapy of Investigator's Choice in Recurrent or Metastatic Head and Neck Carcinoma (CheckMate 141)

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02105636
• Collaborator: Ono Pharmaceutical Co. Ltd (Industry)
• Enrollment: 506
• Locations: 64
• Arms: 2
• Actual Duration (Months): 87.4
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to find out whether Nivolumab will significantly improve overall survival as compared to therapy of investigator's choice in patients with recurrent or metastatic head and neck carcinoma.

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of the Head and Neck	Drug: Nivolumab; Drug: Cetuximab; Drug: Methotrexate; Drug: Docetaxel	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 506 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label, Randomized Phase 3 Clinical Trial of Nivolumab vs Therapy of Investigator's Choice in Recurrent or Metastatic Platinum-refractory Squamous Cell Carcinoma of the Head and Neck (SCCHN)
• Actual Study Start Date: May 29, 2014
• Actual Primary Completion Date: Nov 6, 2015
• Actual Study Completion Date: Sep 10, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: Nivolumab Nivolumab 3mg/kg intravenous (IV) Solution for Injection every 2 weeks until disease progression	Drug: Nivolumab; Other Names: BMS-936558
Active Comparator: Arm B: Cetuximab/Methotrexate/Docetaxel Cetuximab intravenous (IV) Solution for Injection 400 mg/m2 (first dose) then 250 mg/m2 weekly until disease progression OR Methotrexate intravenous (IV) Solution for Injection 40 or 60 mg/m2 weekly until disease progression OR Docetaxel intravenous (IV) Solution for Injection 30 or 40 mg/m2 weekly until disease progression	Drug: Cetuximab; Drug: Methotrexate; Drug: Docetaxel

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) Time in Months for All Randomized Participants at Primary Endpoint [From date of randomization to date of death, approximately 18 months]

   Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Median OS time was calculated using Kaplan-Meier (KM) method. Hazard ratio (HR) and the corresponding Confidence Interval (CI) were estimated in a stratified Cox proportional hazards model for distribution of OS in each randomized arm. Interim analysis (Primary Endpoint) occurred at 218 deaths.

2. Overall Survival (OS) Rate in All Randomized Participants at Primary Endpoint [Randomization to 3, 6, 9, and 12 months]

   The overall survival rate is the probability that a participant will be alive at 3, 6, 9, and 12 months following randomization. Overall survival was defined as the time between the date of randomization and the date of death as a result of any cause. Survival rates were determined via Kaplan-Meier estimates.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [Randomization to disease progression or death, whichever occurs first; Approximately 5 years]

   PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the investigator (as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria), 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 without any on study tumor assessments and did not die were censored on their date of randomization. Participants who received subsequent systemic anti-cancer therapy prior to documented progression were censored at the date of the last tumor assessment prior to the initiation of the new therapy.

2. Objective Response Rate (ORR) [Randomization to disease progression or study drug is discontinued, whichever occurs first; Approximately 5 years]

   ORR was defined as the proportion of randomized participants who achieved a best response of complete response (CR) or partial response (PR) using the RECIST1.1 criteria as per investigator assessment. Best overall response (BOR) was defined as the best response designation, recorded between the date of randomization and the date of progression, as assessed by the investigator per RECIST 1.1 or the date of subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. For participants without evidence of RECIST 1.1 progression or subsequent anticancer therapy, all available response assessments will contribute to the BOR assessment. For participants who continue treatment beyond progression, the BOR was determined based on response assessments up to the time of initial RECIST 1.1 progression.

Other Outcome Measures

1. Number of Participants With Death, Study Drug-Related Death, Serious Adverse Events (SAEs), and Study Drug-Related SAEs in All Treated Participants at Primary Endpoint [Date of first dose of study drug to 30 days post last dose of study drug, approximately 18 months]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Men and women ≥ 18 years of age with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

• Histologically confirmed recurrent or metastatic SCCHN (oral cavity, pharynx, larynx), stage III/IV and not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy)

• Tumor progression or recurrence within 6 months of last dose of platinum therapy in the adjuvant (ie with radiation after surgery), primary (ie, with radiation), recurrent, or metastatic setting

• Measurable disease by Computed tomography (CT) or Magnetic resonance imaging (MRI) per Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria

Exclusion Criteria:

• Active brain metastases or leptomeningeal metastases are not allowed

• Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary, and salivary gland or non-squamous histologies (eg: mucosal melanoma) are not allowed

• Subjects with active, known or suspected autoimmune disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Medical Center	Stanford	California	United States	94305
2	H. Lee Moffitt Cancer Center	Tampa	Florida	United States	33612
3	Winship Cancer Institute	Atlanta	Georgia	United States	30322
4	University Of Chicago	Chicago	Illinois	United States	60637
5	Crescent City Research Consortium, LLC	Metairie	Louisiana	United States	70006
6	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
7	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
8	University Of Michigan	Ann Arbor	Michigan	United States	48109
9	Dumc	Durham	North Carolina	United States	27710
10	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
11	UPMC Cancer Center	Pittsburgh	Pennsylvania	United States	15213
12	Vanderbilt Cancer Clinic	Nashville	Tennessee	United States	37232
13	Univ Of Tx. Md Anderson	Hoston	Texas	United States	77030
14	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
15	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
16	COIBA	Berazategui	Buenos Aires	Argentina	1880
17	Centro Para La Atencion Integral Del Paciente Oncologico	San Miguel De Tucuman	Tucuman	Argentina	4000
18	Instituto Oncologico De Cordoba	Cordoba		Argentina	5000
19	Local Institution	Ijui	Rio Grande Do Sul	Brazil	98700-000
20	Local Institution	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
21	Local Institution	Sao Paulo		Brazil	01321-001
22	BC Cancer - Vancouver	Vancouver	British Columbia	Canada	V5Z 4E6
23	London Regional Cancer Program	London	Ontario	Canada	N6A 4L6
24	Local Institution	Lyon Cedex 08		France	69373
25	Local Institution	Nice Cedex 2		France	06189
26	Local Institution	Villejuif Cedex		France	94805
27	Local Institution	Berlin		Germany	12200
28	Universitaetsklinikum Bonn	Bonn		Germany	53127
29	Universitaetsklinikum Essen	Essen		Germany	45122
30	Uniklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
31	Med Hochschule Hannover	Hannover		Germany	30625
32	Klinikum Der Universitaet	Wuerzburg		Germany	97070
33	Local Institution	Hong Kong		Hong Kong
34	Ist.Scient. Romagnolo Per Lo Studio E Cura Tumori	Meldola	FC	Italy	47014
35	Local Institution	Milano	MI	Italy	20133
36	Local Institution	Torino	TO	Italy	10126
37	Local Institution	Milano		Italy	20142
38	Local Institution	Napoli		Italy	80131
39	Local Institution	Padova		Italy	35128
40	Local Institution	Nagoya	Aichi	Japan	4648681
41	Local Institution	Kashiwa	Chiba	Japan	2778577
42	Local Institution	Sapporo-shi	Hokkaido	Japan	0608648
43	Local Institution	Kobe-shi	Hyogo	Japan	650-0017
44	Local Institution	Takatsuki	Osaka	Japan	5698686
45	Local Institution	Sunto-gun	Shizuoka	Japan	4118777
46	Local Institution	Akashi, Hyogo		Japan	673-8558
47	Local Institution	Tokyo		Japan	135-8550
48	Local Institution	Seoul		Korea, Republic of	135-710
49	Local Institution	Seoul		Korea, Republic of	137-701
50	Local Institution	Amsterdam		Netherlands	1081 HV
51	Local Institution	Groningen		Netherlands	9713 AP
52	Local Institution	Leiden		Netherlands	2333 ZA
53	Local Institution	Barcelona		Spain	08035
54	Local Institution	Barcelona		Spain	08036
55	Local Institution	Madrid		Spain	28041
56	Local Institution	Valencia		Spain	46010
57	Universitatsspital Zurich	Zuerich		Switzerland	8091
58	Local Institution	Tainan		Taiwan	704
59	Local Institution	Taipei		Taiwan	100
60	Local Institution	London	Greater London	United Kingdom	SW3 6JJ
61	Local Institution	Manchester	Greater Manchester	United Kingdom	M20 4BX
62	Local Institution	Southampton	Hampshire	United Kingdom	SO16 6YD
63	Local Institution	Wirral	Merseyside	United Kingdom	CH63 4JY
64	Local Institution	Surrey		United Kingdom	SM2 5PT

Sponsors and Collaborators

• Bristol-Myers Squibb
• Ono Pharmaceutical Co. Ltd

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• Investigator Inquiry Form
• FDA Safety Alerts and Recalls

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02105636
• Other Study ID Numbers: CA209-141; 2013-003622-86
• First Posted: Apr 7, 2014
• Last Update Posted: Jan 4, 2022
• Last Verified: Dec 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Docetaxel; Methotrexate; Nivolumab; Cetuximab

Study Results

Participant Flow

Recruitment Details	506 enrolled, 361 randomized. Non-randomized reasons: 5 adverse events, 18 withdrew consent, 7 died, 108 no longer met study criteria, 7 other. 347 treated (236 nivo, 111 IC). Non-treatment reasons: 1 disease progression, 3 request to discontinue treatment, 6 withdrew consent, 4 no longer met study criteria. Nivo=nivolumab, IC=investigator's choice

Arm/Group Title	Nivolumab 3mg/kg	Cetuximab/Methotrexate/Docetaxel
Arm/Group Description	Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.	Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligram/meter squared (mg/m2) for the first dose followed that a doses of 250 mg/m2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice.
Period Title: Overall Study
STARTED	236	111
COMPLETED	41	3
NOT COMPLETED	195	108

Baseline Characteristics

Arm/Group Title	Nivolumab 3mg/kg	Cetuximab/Methotrexate/Docetaxel	Total
Arm/Group Description	Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.	Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligram/meter squared (mg/m2) for the first dose followed that a doses of 250 mg/m2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice.	Total of all reporting groups
Overall Participants	240	121	361
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.0 (10.15)	59.4 (11.00)	59.1 (10.43)
Age, Customized (participants) [Number]
< 65 years	172 71.7%	76 62.8%	248 68.7%
>=65 and <75 years	56 23.3%	39 32.2%	95 26.3%
>=75 years	12 5%	6 5%	18 5%
Sex: Female, Male (Count of Participants)
Female	43 17.9%	18 14.9%	61 16.9%
Male	197 82.1%	103 85.1%	300 83.1%
Race/Ethnicity, Customized (participants) [Number]
White	196 81.7%	104 86%	300 83.1%
Black or African American	10 4.2%	3 2.5%	13 3.6%
Asian	29 12.1%	14 11.6%	43 11.9%
Other	5 2.1%	0 0%	5 1.4%
Race/Ethnicity, Customized (participants) [Number]
Hispanic/Latino	9 3.8%	4 3.3%	13 3.6%
Not Hispanic/Latino	132 55%	60 49.6%	192 53.2%
Not Reported	99 41.3%	57 47.1%	156 43.2%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
0	49 20.4%	23 19%	72 19.9%
1	189 78.8%	94 77.7%	283 78.4%
>=2	1 0.4%	3 2.5%	4 1.1%
Not Reported	1 0.4%	1 0.8%	2 0.6%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) Time in Months for All Randomized Participants at Primary Endpoint
Description	Overall survival was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Median OS time was calculated using Kaplan-Meier (KM) method. Hazard ratio (HR) and the corresponding Confidence Interval (CI) were estimated in a stratified Cox proportional hazards model for distribution of OS in each randomized arm. Interim analysis (Primary Endpoint) occurred at 218 deaths.
Time Frame	From date of randomization to date of death, approximately 18 months

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	Nivolumab 3mg/kg	Cetuximab/Methotrexate/Docetaxel
Arm/Group Description	Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.	Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligram/meter squared (mg/m2) for the first dose followed that a doses of 250 mg/m2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice.
Measure Participants	240	121
Median (95% Confidence Interval) [months]	7.49	5.06

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab 3mg/kg, Cetuximab/Methotrexate/Docetaxel
	Comments	Stratified Cox proportional hazard model. HR = Nivolumab over investigator's choice therapy (Cetuximab, Methotrexate, or Docetaxel)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0101
	Comments	Log-rank Test stratified by prior treatment with cetuximab (yes, no) as entered into the Interactive Voice Response System (IVRS). For OS the boundary for statistical significance requires the p-value to be less than 0.0227.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Overall Survival (OS) Rate in All Randomized Participants at Primary Endpoint
Description	The overall survival rate is the probability that a participant will be alive at 3, 6, 9, and 12 months following randomization. Overall survival was defined as the time between the date of randomization and the date of death as a result of any cause. Survival rates were determined via Kaplan-Meier estimates.
Time Frame	Randomization to 3, 6, 9, and 12 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab 3mg/kg	Cetuximab/Methotrexate/Docetaxel
Arm/Group Description	Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.	Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligram/meter squared (mg/m2) for the first dose followed that a doses of 250 mg/m2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice.
Measure Participants	240	121
3 months	71.5	74.0
6 months	55.6	41.8
9 months	43.4	29.1
12 months	36.0	16.6

3. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the investigator (as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria), 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 without any on study tumor assessments and did not die were censored on their date of randomization. Participants who received subsequent systemic anti-cancer therapy prior to documented progression were censored at the date of the last tumor assessment prior to the initiation of the new therapy.
Time Frame	Randomization to disease progression or death, whichever occurs first; Approximately 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR was defined as the proportion of randomized participants who achieved a best response of complete response (CR) or partial response (PR) using the RECIST1.1 criteria as per investigator assessment. Best overall response (BOR) was defined as the best response designation, recorded between the date of randomization and the date of progression, as assessed by the investigator per RECIST 1.1 or the date of subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. For participants without evidence of RECIST 1.1 progression or subsequent anticancer therapy, all available response assessments will contribute to the BOR assessment. For participants who continue treatment beyond progression, the BOR was determined based on response assessments up to the time of initial RECIST 1.1 progression.
Time Frame	Randomization to disease progression or study drug is discontinued, whichever occurs first; Approximately 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Number of Participants With Death, Study Drug-Related Death, Serious Adverse Events (SAEs), and Study Drug-Related SAEs in All Treated Participants at Primary Endpoint
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug.
Time Frame	Date of first dose of study drug to 30 days post last dose of study drug, approximately 18 months

Outcome Measure Data

Analysis Population Description

All Treated Participants: All randomized participants who received at least one dose of study drug

Arm/Group Title	Nivolumab 3mg/kg	Cetuximab/Methotrexate/Docetaxel
Arm/Group Description	Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.	Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligram/meter squared (mg/m2) for the first dose followed that a doses of 250 mg/m2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigator's Choice.
Measure Participants	236	111
Deaths	50 20.8%	21 17.4%
Study Drug-Related Deaths	2 0.8%	0 0%
SAEs	127 52.9%	66 54.5%
Study Drug-Related SAEs	16 6.7%	17 14%
AEs Leading to Discontinuation	51 21.3%	27 22.3%
Study Drug-Related AEs Leading to Discontinuation	9 3.8%	11 9.1%

Adverse Events

Time Frame	From first dose to last dose plus 30 days up to Primary Endpoint, approximately 18 months (November 2015)
Adverse Event Reporting Description	Study initiated: May 2014; Primary Endpoint: November 2015 (study on-going)
Arm/Group Title	Nivolumab 3 mg/kg		Cetuximab/Methotrexate/Docetaxel
Arm/Group Description	Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.		Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligram/meter squared (mg/m2) for the first dose followed that a doses of 250 mg/m2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice.
All Cause Mortality
	Nivolumab 3 mg/kg		Cetuximab/Methotrexate/Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nivolumab 3 mg/kg		Cetuximab/Methotrexate/Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	127/236 (53.8%)		66/111 (59.5%)
Blood and lymphatic system disorders
Anaemia	0/236 (0%)		2/111 (1.8%)
Leukopenia	0/236 (0%)		1/111 (0.9%)
Cardiac disorders
Acute myocardial infarction	1/236 (0.4%)		0/111 (0%)
Atrial flutter	1/236 (0.4%)		1/111 (0.9%)
Cardiac arrest	0/236 (0%)		1/111 (0.9%)
Cardiac failure	2/236 (0.8%)		0/111 (0%)
Cardio-respiratory arrest	1/236 (0.4%)		0/111 (0%)
Atrial fibrillation	0/236 (0%)		1/111 (0.9%)
Pericarditis	1/236 (0.4%)		0/111 (0%)
Cardiovascular disorder	0/236 (0%)		1/111 (0.9%)
Supraventricular tachycardia	0/236 (0%)		1/111 (0.9%)
Cardiopulmonary failure	1/236 (0.4%)		0/111 (0%)
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula	0/236 (0%)		1/111 (0.9%)
Ear and labyrinth disorders
Vertigo	0/236 (0%)		1/111 (0.9%)
Endocrine disorders
Hypophysitis	1/236 (0.4%)		0/111 (0%)
Secondary hypothyroidism	1/236 (0.4%)		0/111 (0%)
Secondary adrenocortical insufficiency	1/236 (0.4%)		0/111 (0%)
Eye disorders
Visual acuity reduced	0/236 (0%)		1/111 (0.9%)
Blindness unilateral	1/236 (0.4%)		0/111 (0%)
Gastrointestinal disorders
Abdominal pain	1/236 (0.4%)		2/111 (1.8%)
Colitis	0/236 (0%)		1/111 (0.9%)
Gastric haemorrhage	1/236 (0.4%)		0/111 (0%)
Gastritis	0/236 (0%)		1/111 (0.9%)
Gastric disorder	1/236 (0.4%)		0/111 (0%)
Nausea	0/236 (0%)		1/111 (0.9%)
Pneumoperitoneum	1/236 (0.4%)		0/111 (0%)
Stomatitis	1/236 (0.4%)		1/111 (0.9%)
Tongue haemorrhage	2/236 (0.8%)		0/111 (0%)
Parotid gland haemorrhage	1/236 (0.4%)		0/111 (0%)
Diarrhoea	0/236 (0%)		2/111 (1.8%)
Oesophageal stenosis	1/236 (0.4%)		0/111 (0%)
Dysphagia	2/236 (0.8%)		3/111 (2.7%)
General disorders
Face oedema	0/236 (0%)		1/111 (0.9%)
Asthenia	1/236 (0.4%)		2/111 (1.8%)
Pyrexia	3/236 (1.3%)		4/111 (3.6%)
Mucosal inflammation	0/236 (0%)		1/111 (0.9%)
Pain	0/236 (0%)		1/111 (0.9%)
General physical health deterioration	0/236 (0%)		1/111 (0.9%)
Catheter site pain	1/236 (0.4%)		0/111 (0%)
Localised oedema	1/236 (0.4%)		0/111 (0%)
Malaise	0/236 (0%)		2/111 (1.8%)
Ulcer haemorrhage	1/236 (0.4%)		0/111 (0%)
Disease progression	1/236 (0.4%)		0/111 (0%)
Drug intolerance	0/236 (0%)		1/111 (0.9%)
Chills	1/236 (0.4%)		1/111 (0.9%)
Device occlusion	0/236 (0%)		1/111 (0.9%)
Fatigue	2/236 (0.8%)		1/111 (0.9%)
Immune system disorders
Allergic granulomatous angiitis	1/236 (0.4%)		0/111 (0%)
Infections and infestations
Infection	2/236 (0.8%)		0/111 (0%)
Respiratory tract infection	5/236 (2.1%)		1/111 (0.9%)
Skin infection	0/236 (0%)		1/111 (0.9%)
Lower respiratory tract infection	3/236 (1.3%)		3/111 (2.7%)
Peritonitis	1/236 (0.4%)		0/111 (0%)
Pneumonia bacterial	1/236 (0.4%)		0/111 (0%)
Lymphangitis	1/236 (0.4%)		0/111 (0%)
Otitis media	1/236 (0.4%)		0/111 (0%)
Upper respiratory tract infection	0/236 (0%)		1/111 (0.9%)
Tracheitis	1/236 (0.4%)		0/111 (0%)
Urinary tract infection	4/236 (1.7%)		0/111 (0%)
Cellulitis	0/236 (0%)		1/111 (0.9%)
Gastrointestinal infection	0/236 (0%)		1/111 (0.9%)
Neutropenic sepsis	1/236 (0.4%)		1/111 (0.9%)
Purulent discharge	1/236 (0.4%)		0/111 (0%)
Clostridium difficile colitis	1/236 (0.4%)		1/111 (0.9%)
Pneumonia	10/236 (4.2%)		1/111 (0.9%)
Sepsis	5/236 (2.1%)		3/111 (2.7%)
Device related infection	0/236 (0%)		2/111 (1.8%)
Localised infection	1/236 (0.4%)		1/111 (0.9%)
Lung infection	4/236 (1.7%)		4/111 (3.6%)
Wound infection	1/236 (0.4%)		1/111 (0.9%)
Injury, poisoning and procedural complications
Wound haemorrhage	1/236 (0.4%)		0/111 (0%)
Post procedural haemorrhage	1/236 (0.4%)		1/111 (0.9%)
Tracheostomy malfunction	1/236 (0.4%)		0/111 (0%)
Vascular pseudoaneurysm ruptured	1/236 (0.4%)		0/111 (0%)
Infusion related reaction	1/236 (0.4%)		1/111 (0.9%)
Investigations
Blood alkaline phosphatase increased	1/236 (0.4%)		0/111 (0%)
Blood bilirubin increased	1/236 (0.4%)		0/111 (0%)
Liver function test abnormal	1/236 (0.4%)		0/111 (0%)
Platelet count decreased	0/236 (0%)		1/111 (0.9%)
Transaminases increased	1/236 (0.4%)		0/111 (0%)
Metabolism and nutrition disorders
Hypernatraemia	0/236 (0%)		1/111 (0.9%)
Malnutrition	2/236 (0.8%)		0/111 (0%)
Hyponatraemia	2/236 (0.8%)		0/111 (0%)
Hypophagia	1/236 (0.4%)		0/111 (0%)
Decreased appetite	4/236 (1.7%)		1/111 (0.9%)
Dehydration	3/236 (1.3%)		0/111 (0%)
Hyperglycaemia	1/236 (0.4%)		0/111 (0%)
Hypophosphataemia	1/236 (0.4%)		0/111 (0%)
Hypercalcaemia	3/236 (1.3%)		1/111 (0.9%)
Musculoskeletal and connective tissue disorders
Back pain	2/236 (0.8%)		0/111 (0%)
Bone pain	1/236 (0.4%)		0/111 (0%)
Musculoskeletal chest pain	1/236 (0.4%)		0/111 (0%)
Pain in extremity	1/236 (0.4%)		0/111 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage	2/236 (0.8%)		0/111 (0%)
Cancer pain	1/236 (0.4%)		0/111 (0%)
Head and neck cancer	1/236 (0.4%)		0/111 (0%)
Tumour pain	0/236 (0%)		1/111 (0.9%)
Malignant pleural effusion	1/236 (0.4%)		0/111 (0%)
Neoplasm malignant	1/236 (0.4%)		0/111 (0%)
Metastases to central nervous system	1/236 (0.4%)		0/111 (0%)
Malignant neoplasm progression	43/236 (18.2%)		25/111 (22.5%)
Nervous system disorders
Cerebrovascular accident	1/236 (0.4%)		0/111 (0%)
Headache	0/236 (0%)		1/111 (0.9%)
Neuralgia	0/236 (0%)		1/111 (0.9%)
Syncope	1/236 (0.4%)		1/111 (0.9%)
Hydrocephalus	1/236 (0.4%)		0/111 (0%)
Speech disorder	1/236 (0.4%)		0/111 (0%)
Dizziness	0/236 (0%)		2/111 (1.8%)
Encephalopathy	1/236 (0.4%)		0/111 (0%)
Ischaemic stroke	1/236 (0.4%)		0/111 (0%)
Complex partial seizures	1/236 (0.4%)		0/111 (0%)
Psychiatric disorders
Delirium	1/236 (0.4%)		0/111 (0%)
Agoraphobia	0/236 (0%)		1/111 (0.9%)
Renal and urinary disorders
Acute kidney injury	0/236 (0%)		1/111 (0.9%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/236 (0.4%)		0/111 (0%)
Dyspnoea	9/236 (3.8%)		1/111 (0.9%)
Laryngeal stenosis	1/236 (0.4%)		0/111 (0%)
Obstructive airways disorder	1/236 (0.4%)		0/111 (0%)
Hypoxia	0/236 (0%)		1/111 (0.9%)
Bronchopneumopathy	0/236 (0%)		1/111 (0.9%)
Pneumothorax	1/236 (0.4%)		0/111 (0%)
Pneumothorax spontaneous	1/236 (0.4%)		0/111 (0%)
Pharyngeal oedema	1/236 (0.4%)		0/111 (0%)
Respiratory distress	1/236 (0.4%)		2/111 (1.8%)
Haemoptysis	2/236 (0.8%)		1/111 (0.9%)
Pneumonia aspiration	8/236 (3.4%)		2/111 (1.8%)
Laryngeal oedema	1/236 (0.4%)		1/111 (0.9%)
Pleural effusion	2/236 (0.8%)		3/111 (2.7%)
Stridor	2/236 (0.8%)		0/111 (0%)
Pneumonitis	2/236 (0.8%)		0/111 (0%)
Respiratory failure	4/236 (1.7%)		0/111 (0%)
Skin and subcutaneous tissue disorders
Dermatomyositis	0/236 (0%)		1/111 (0.9%)
Angioedema	0/236 (0%)		1/111 (0.9%)
Skin mass	1/236 (0.4%)		0/111 (0%)
Skin ulcer	1/236 (0.4%)		0/111 (0%)
Vascular disorders
Haematoma	0/236 (0%)		1/111 (0.9%)
Hypertensive crisis	1/236 (0.4%)		0/111 (0%)
Superior vena cava syndrome	1/236 (0.4%)		0/111 (0%)
Hypovolaemic shock	0/236 (0%)		1/111 (0.9%)
Shock haemorrhagic	1/236 (0.4%)		0/111 (0%)
Haemorrhage	1/236 (0.4%)		0/111 (0%)
Hypotension	0/236 (0%)		1/111 (0.9%)
Other (Not Including Serious) Adverse Events
	Nivolumab 3 mg/kg		Cetuximab/Methotrexate/Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	202/236 (85.6%)		105/111 (94.6%)
Blood and lymphatic system disorders
Thrombocytopenia	3/236 (1.3%)		6/111 (5.4%)
Neutropenia	1/236 (0.4%)		9/111 (8.1%)
Anaemia	44/236 (18.6%)		36/111 (32.4%)
Cardiac disorders
Tachycardia	3/236 (1.3%)		6/111 (5.4%)
Endocrine disorders
Hypothyroidism	15/236 (6.4%)		6/111 (5.4%)
Eye disorders
Lacrimation increased	1/236 (0.4%)		6/111 (5.4%)
Gastrointestinal disorders
Gastrooesophageal reflux disease	2/236 (0.8%)		8/111 (7.2%)
Constipation	36/236 (15.3%)		20/111 (18%)
Nausea	45/236 (19.1%)		34/111 (30.6%)
Stomatitis	7/236 (3%)		11/111 (9.9%)
Vomiting	27/236 (11.4%)		14/111 (12.6%)
Dry mouth	7/236 (3%)		6/111 (5.4%)
Diarrhoea	35/236 (14.8%)		25/111 (22.5%)
Dysphagia	28/236 (11.9%)		13/111 (11.7%)
General disorders
Face oedema	10/236 (4.2%)		8/111 (7.2%)
Oedema peripheral	18/236 (7.6%)		5/111 (4.5%)
Asthenia	24/236 (10.2%)		23/111 (20.7%)
Pyrexia	29/236 (12.3%)		12/111 (10.8%)
Mucosal inflammation	8/236 (3.4%)		17/111 (15.3%)
Fatigue	62/236 (26.3%)		35/111 (31.5%)
Infections and infestations
Respiratory tract infection	4/236 (1.7%)		6/111 (5.4%)
Oral candidiasis	6/236 (2.5%)		6/111 (5.4%)
Investigations
Aspartate aminotransferase increased	12/236 (5.1%)		4/111 (3.6%)
Blood alkaline phosphatase increased	17/236 (7.2%)		3/111 (2.7%)
Weight decreased	31/236 (13.1%)		16/111 (14.4%)
Metabolism and nutrition disorders
Hyponatraemia	21/236 (8.9%)		14/111 (12.6%)
Decreased appetite	41/236 (17.4%)		21/111 (18.9%)
Hyperglycaemia	12/236 (5.1%)		9/111 (8.1%)
Hypercalcaemia	15/236 (6.4%)		7/111 (6.3%)
Hypokalaemia	8/236 (3.4%)		8/111 (7.2%)
Musculoskeletal and connective tissue disorders
Back pain	12/236 (5.1%)		0/111 (0%)
Neck pain	12/236 (5.1%)		8/111 (7.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	13/236 (5.5%)		6/111 (5.4%)
Nervous system disorders
Headache	21/236 (8.9%)		3/111 (2.7%)
Neuropathy peripheral	4/236 (1.7%)		8/111 (7.2%)
Psychiatric disorders
Insomnia	12/236 (5.1%)		7/111 (6.3%)
Anxiety	8/236 (3.4%)		7/111 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	32/236 (13.6%)		10/111 (9%)
Dyspnoea	27/236 (11.4%)		11/111 (9.9%)
Productive cough	12/236 (5.1%)		2/111 (1.8%)
Epistaxis	4/236 (1.7%)		11/111 (9.9%)
Pleural effusion	5/236 (2.1%)		6/111 (5.4%)
Skin and subcutaneous tissue disorders
Rash	20/236 (8.5%)		5/111 (4.5%)
Pruritus	20/236 (8.5%)		0/111 (0%)
Dry skin	11/236 (4.7%)		12/111 (10.8%)
Erythema	3/236 (1.3%)		6/111 (5.4%)
Alopecia	2/236 (0.8%)		14/111 (12.6%)
Vascular disorders
Hypertension	14/236 (5.9%)		3/111 (2.7%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

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.