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Clinical Trial Results:
A Randomized Double-blind Phase 3 Study of Avelumab in Combination With Standard of Care Chemoradiotherapy (Cisplatin Plus Definitive Radiation Therapy) Versus Standard of Care Chemoradiotherapy in the Front-line Treatment of Patients With Locally Advanced Squamous cell Carcinoma of The Head and Neck.

Summary
EudraCT number	2016-001456-21
Trial protocol	GB BE DE PL AT ES IE PT HU FR GR IT
Global end of trial date	25 Aug 2020

Results information
Results version number	v1(current)
This version publication date	21 Aug 2021
First version publication date	21 Aug 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

B9991016

ISRCTN number

-

US NCT number

NCT02952586

WHO universal trial number (UTN)

-

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States,

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

19 Feb 2021

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

25 Aug 2020

Was the trial ended prematurely?

Yes

Main objective of the trial

To demonstrate that treatment with avelumab in combination with Standard of Care Chemotherapy (SOC CRT) was superior to SOC CRT alone in prolonging Progression-free Survival (PFS) in front-line subjects with high risk, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) who were candidates for definitive CRT with cisplatin.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

28 Nov 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

28 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

United States: 173

Country: Number of subjects enrolled

China: 45

Country: Number of subjects enrolled

Japan: 51

Country: Number of subjects enrolled

Korea, Republic of: 19

Country: Number of subjects enrolled

Taiwan: 69

Country: Number of subjects enrolled

Australia: 10

Country: Number of subjects enrolled

Hungary: 43

Country: Number of subjects enrolled

Poland: 16

Country: Number of subjects enrolled

Russian Federation: 38

Country: Number of subjects enrolled

Israel: 13

Country: Number of subjects enrolled

Austria: 4

Country: Number of subjects enrolled

Belgium: 19

Country: Number of subjects enrolled

France: 53

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Greece: 23

Country: Number of subjects enrolled

Ireland: 3

Country: Number of subjects enrolled

Italy: 19

Country: Number of subjects enrolled

Portugal: 30

Country: Number of subjects enrolled

Spain: 31

Country: Number of subjects enrolled

Switzerland: 12

Country: Number of subjects enrolled

United Kingdom: 17

Worldwide total number of subjects

697

EEA total number of subjects

249

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

495

From 65 to 84 years

201

85 years and over

1

Subject disposition

Top of page

Recruitment details

Study had 3 sequential treatment phases: Lead-in,CRT and Maintenance. There were 3 treatments administered during CRT phase: Blinded therapy (Avelumab/placebo), Cisplatin and IMRT. Only blinded therapy (Avelumab/placebo) was administered during Lead-in and Maintenance phases. Reasons for discontinuation are summarized separately for each treatment.

Screening details

If a subject discontinued all 3 treatments due to death, then death is included as reason for discontinuation in each treatment disposition summary. All deaths that are reported as reason for discontinuation at any phase are included in all-cause mortality summary.

Period 1 title

Lead-In Phase (7 Days)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Arm description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

Experimental

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Subjects were administered with avelumab 10 mg/kg IV injection on Day 1 of the Lead-in Phase.

Placebo + SOC CRT

Arm description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Subjects were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days).

Number of subjects in period 1	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Started	350	347
Safety Analysis Set	348	344
Completed	345	343
Not completed	5	4
Adverse event, non-fatal	3	-
Death	-	1
No Longer Met Eligibility Criteria	-	1
Withdrawal by subject	2	2

Period 2 title

CRT for Avelumab or Placebo (63 Days)

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Arm description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

Experimental

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Subjects were administered with avelumab 10 mg/kg IV injection on Days 8, 25 and 39 in CRT phase.

Placebo + SOC CRT

Arm description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Subjects were administered with avelumab matching placebo 10 mg/kg IV injection on Days 8, 25 and 39 in CRT phase.

Number of subjects in period 2 ^[1]	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Started	345	340
Completed	312	313
Not completed	33	27
Physician decision	2	1
Adverse event, non-fatal	12	12
Death	5	8
Unspecified	2	1
Lost to follow-up	1	1
Global Deterioration of Health Status	1	-
Withdrawal by subject	10	4

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: All subjects who did not withdraw from study after Lead-In phase, entered into CRT phase.

Period 3 title

CRT for Cisplatin (63 Days)

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Arm description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

Experimental

Investigational medicinal product name

Cisplastin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Cisplatin 100 mg/m^2 IV injection on Days 1, 22 and 43 of CRT phase.

Placebo + SOC CRT

Arm description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

Placebo

Investigational medicinal product name

Cisplastin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Cisplatin 100 mg/m^2 IV injection on Days 1, 22 and 43 of CRT phase.

Number of subjects in period 3	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Started	312	313
Completed	234	236
Not completed	111	104
Physician decision	12	10
Adverse event, non-fatal	82	81
Death	3	8
Unspecified	1	1
Lost to follow-up	1	1
Global Deterioration of Health Status	1	-
Withdrawal by subject	11	3
Joined	33	27
Continued in this period	33	27

Period 4 title

CRT for IMRT (63 Days)

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Arm description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Placebo + SOC CRT

Arm description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 4	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Started	234	236
Completed	322	320
Not completed	23	20
Adverse event, non-fatal	5	5
Death	5	8
Unspecified	1	-
Lost to follow-up	1	1
Global Deterioration of Health Status	1	-
Withdrawal by subject	10	6
Joined	111	104
Continued in this period	111	104

Period 5 title

Maintenance Phase (MP) (12 Months)

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Arm description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

Experimental

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 10 mg/kg IV injection every 2 weeks for up to 12 months.

Placebo + SOC CRT

Arm description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 10 mg/kg matching placebo IV injection every 2 weeks for up to 12 months.

Number of subjects in period 5 ^[2]	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Started	291	304
Completed	139	177
Not completed	152	127
Physician decision	1	1
Adverse event, non-fatal	24	21
Non-compliance With Study Drug	1	1
Death	17	11
Unspecified	2	1
Study Terminated by Sponsor	1	6
Progressive disease	60	54
Lost to follow-up	1	2
Global Deterioration of Health Status	14	5
Withdrawal by subject	31	25

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: All subjects who did not withdraw from the CRT phase entered MP

Period 6 title

Follow-Up Phase (FUP) (90 Days)

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Arm description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Placebo + SOC CRT

Arm description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 6	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Started	139	177
Completed	208	216
Not completed	58	68
Death	12	10
Unspecified	7	5
Study Terminated by Sponsor	32	50
Lost to follow-up	1	1
Withdrawal by subject	6	2
Joined	127	107
Continued in this period	127	107

Period 7 title

LT Follow-up (up to 45 months)

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Arm description

Ssubjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Placebo + SOC CRT

Arm description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 7	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Started	208	216
Completed	0	0
Not completed	247	237
Death	51	31
Study Terminated by Sponsor	187	201
Lost to follow-up	2	4
Withdrawal by subject	7	1
Joined	39	21
Continued in this period	39	21

Baseline characteristics

Top of page

Reporting group title

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Reporting group description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Placebo + SOC CRT

Reporting group description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT	Total
Number of subjects	350	347	697
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	248	247	495
From 65-84 years	102	99	201
85 years and over	0	1	1
Age Continuous
Units: years
arithmetic mean (standard deviation)	59.36 ± 8.56	58.88 ± 9.09	-
Sex: Female, Male
Units: subjects
Female	60	62	122
Male	290	285	575
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	13	8	21
Not Hispanic or Latino	312	312	624
Unknown or Not Reported	25	27	52
Race/Ethnicity, Customized
Units: Subjects
Black or African American	9	10	19
American Indian or Alaska Native	1	0	1
Asian	102	86	188
Native Hawaiian or Other Pacific Islander	0	1	1
White	224	229	453
Other	14	21	35

End points

Top of page

Reporting group title

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Reporting group description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Placebo + SOC CRT

Reporting group description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Reporting group description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Placebo + SOC CRT

Reporting group description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Reporting group description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Placebo + SOC CRT

Reporting group description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Reporting group description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Placebo + SOC CRT

Reporting group description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Reporting group description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Placebo + SOC CRT

Reporting group description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Reporting group description

Subjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Placebo + SOC CRT

Reporting group description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Reporting group description

Ssubjects with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received avelumab 10 mg/kg IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Placebo + SOC CRT

Reporting group description

Subjects with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase subjects also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which subjects received placebo IV injection every 2 weeks. All subjects were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose subjects were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Primary: Progression-free Survival (PFS) per Modified Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) as Assessed by Investigator

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End point title

Progression-free Survival (PFS) per Modified Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) as Assessed by Investigator

End point description

PFS= Time (in months) from date of randomization to first documented objective PD per modified RECIST v1.1 as assessed by Investigator or death (by any cause), whichever occurred first. Analysis was performed by Kaplan Meier method. PD=any of following: 1) Locoregional PD confirmed by pathology to verify radiographic changes represent true tumor progression and not radiation effects or non-malignant contrast enhancement. 2) Locoregional clinically detectable progression confirmed by pathology. 3) Salvage of primary tumor with tumor present on final pathology. 4) Salvage neck dissection >20 weeks after completion of CRT with tumor present on final pathology. 5) Metastatic PD. PFS data was censored on date of last adequate tumor assessment for subjects with no PFS event. FAS used. 99999=Median and upper limit of 95% CI were not reached at time of PCD. At time of pre-specified interim analysis for endpoint, futility boundaries for Avelumab +SOC CRT arm was crossed and study terminated.

End point type

Primary

End point timeframe

From randomization until documented PD or death, censored date, whichever occurred first (up to 37 months)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	350	347
Units: months
median (confidence interval 95%)	99999 (16.9 to 99999)	99999 (23.0 to 99999)

PFS analysis (Avelumab+SOC CRT Vs Placebo+SOC CRT)

Comparison groups

Placebo + SOC CRT v Avelumab + Standard of Care Chemotherapy (SOC CRT)

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9199 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.928

upper limit

1.573

Notes
[1] - The treatment arms were compared using a stratified, 1-sided, log rank Test. The three stratification factors were tumor (T) stage (< T4 vs T4), Nodal (N) stage (N0 /N1/N2a/N2b vs N2c/N3), Human papillomavirus (HPV) status (Positive vs Negative).

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Subjects last known to be alive were censored at date of last contact. Analysis was performed using Kaplan Meier method. FAS included all randomized subjects. 99999=Median and 95% CI were not reached at the time of primary completion date. At the time of pre-specified interim analysis for the endpoint, the futility boundaries for the Avelumab +SOC CRT arm was crossed and the study was terminated.

End point type

Secondary

End point timeframe

From randomization to the date of death or censored date, whichever occurred first (up to 37 months)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	350	347
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

OS analysis (Avelumab+SOC CRT Vs Placebo+SOC CRT)

Comparison groups

Avelumab + Standard of Care Chemotherapy (SOC CRT) v Placebo + SOC CRT

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9372 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.927

upper limit

1.849

Notes
[2] - The treatment arms were compared using a stratified, 1-sided, log rank Test. The three stratification factors were tumor (T) stage (< T4 vs T4), Nodal (N) stage (N0 /N1/N2a/N2b vs N2c/N3), Human papillomavirus (HPV) status (Positive vs Negative).

Secondary: Pathologic Complete Response (pCR) Rate in Subjects With Salvage Surgery at the Primary Site

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End point title

Pathologic Complete Response (pCR) Rate in Subjects With Salvage Surgery at the Primary Site

End point description

pCR was defined as the absence of histologically identifiable residual cancer in any resected specimen. The pCR rate at primary site was estimated by dividing the number of subjects with pCR recorded at any visit from randomization until PD per modified RECIST v1.1 or death due to any cause by the number of subjects randomised who had salvage surgery at the primary site. All randomized subjects who had salvage surgery at the primary site.

End point type

Secondary

End point timeframe

From randomization until PD or death (up to 37 months)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	6	7
Units: percentage of subjects
number (confidence interval 95%)	0 (0.0 to 45.9)	14.3 (0.4 to 57.9)

No statistical analyses for this end point

Secondary: Time to Locoregional Failure per Modified RECIST v1.1 as Assessed by Investigator

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End point title

Time to Locoregional Failure per Modified RECIST v1.1 as Assessed by Investigator

End point description

Locoregional failure was defined as the time from the date of randomization to the date of the first documentation of locoregional recurrence per modified RECIST v1.1 as assessed by Investigator or death due to any cause , whichever occurred first. Analysis was performed using Kaplan Meier method. Here, "99999" indicated median and upper limit of 95% CI were not reached. FAS included all randomized subjects.

End point type

Secondary

End point timeframe

From the date of randomization to the date of the first documentation of locoregional recurrence or death, whichever occurred first (up to 37 months)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	350	347
Units: months
median (confidence interval 95%)	99999 (22.4 to 99999)	99999 (25.0 to 99999)

Avelumab + SOC CRT Vs Placebo + SOC CRT

Comparison groups

Avelumab + Standard of Care Chemotherapy (SOC CRT) v Placebo + SOC CRT

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9316 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.694

Notes
[3] - The treatment arms were compared using a stratified, 1-sided, log rank Test. The three stratification factors were tumor (T) stage (< T4 vs T4), Nodal (N) stage (N0 /N1/N2a/N2b vs N2c/N3), Human papillomavirus (HPV) status (Positive vs Negative).

Secondary: Objective Response Rate (ORR) per Modified RECIST v1.1 as Assessed by Investigator

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End point title

Objective Response Rate (ORR) per Modified RECIST v1.1 as Assessed by Investigator

End point description

Objective response (OR) was defined as a complete response (CR) or partial response (PR) per RECIST v1.1 recorded from randomization until disease progression per modified RECIST v1.1 or death due to any cause. A subject was considered to have achieved an OR if the subject had a CR or PR which did not need to be confirmed at a subsequent assessment. CR for target disease: complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis less than [<] 10 millimeter [mm]). CR for non-target disease: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be ‘normal’ in size (<10 mm short axis). PR: Greater than or equal to (>=) 30% decrease under baseline of the sum of diameters of all target measurable lesions. The ORR was estimated by dividing the number of subjects with OR (CR or PR) by the number of subjects randomized. FAS included all randomized subjects.

End point type

Secondary

End point timeframe

From randomization until disease progression or death, whichever occurred first (up to 37 months)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	350	347
Units: percentage of subjects
number (confidence interval 95%)	74.0 (69.1 to 78.5)	74.9 (70.0 to 79.4)

ORR analysis (Avelumab+SOC CRT Vs Placebo+SOC CRT)

Comparison groups

Avelumab + Standard of Care Chemotherapy (SOC CRT) v Placebo + SOC CRT

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6229 ^[4]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.947

Confidence interval

level

95%

sides

2-sided

lower limit

0.663

upper limit

1.352

Notes
[4] - The treatment arms were compared using a stratified, 1-sided, Cochran-Mantel-Haenszel Test. The 3 stratification factors were tumor stage (< T4 vs T4), Nodal stage (N0 /N1/N2a/N2b vs N2c/N3), HPV status (Positive vs Negative).

Secondary: Time to Distant Metastatic Failure per Modified RECIST v1.1 as Assessed by Investigator

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End point title

Time to Distant Metastatic Failure per Modified RECIST v1.1 as Assessed by Investigator

End point description

Time to distant metastatic failure or distant metastasis (DM) was defined as the time from the date of randomization to the date of the first documentation of distant metastasis or death due to any cause, whichever occurred first. Distant metastatic disease was defined as new tumor identified at a site distant from the head and neck anatomic region or draining lymph nodes. Analysis was performed using Kaplan Meier method. FAS included all randomized subjects. 99999=Median and upper limit of 95% CI were not reached at the time of primary completion date. At the time of pre-specified interim analysis for the outcome measure, the futility boundaries for the Avelumab +SOC CRT arm was crossed and the study was terminated.

End point type

Secondary

End point timeframe

From the date of randomization to the date of the first documentation of distant metastatic or death (up to 37 months)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	350	347
Units: months
median (confidence interval 95%)	99999 (22.8 to 99999)	99999 (99999 to 99999)

Avelumab + SOC CRT Vs Placebo + SOC CRT

Comparison groups

Avelumab + Standard of Care Chemotherapy (SOC CRT) v Placebo + SOC CRT

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9061 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.909

upper limit

1.624

Notes
[5] - The treatment arms were compared using a stratified, 1-sided, log rank Test. The three stratification factors were tumor stage (< T4 vs T4), Nodal stage (N0 /N1/N2a/N2b vs N2c/N3), HPV status (Positive vs Negative).

Secondary: Duration of Response (DOR) per modified RECIST v1.1 as Assessed by Investigator

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End point title

Duration of Response (DOR) per modified RECIST v1.1 as Assessed by Investigator

End point description

DOR:time from 1st documentation of objective tumor response (CR/PR) to first documentation of PD/death (any cause),whichever occurred first.PR:>=30% decrease under baseline of sum of diameters of all target measurable lesions. CR(Target disease):Complete disappearance of all target lesions with exception of nodal disease.CR(non-target disease):disappearance of all non-target lesions and normalization of tumor marker levels PD is anyone:1)Locoregional PD confirmed by pathology to verify radiographic changes denote true tumor progression and not radiation effects or non-malignant contrast boost.2)Locoregional clinically detectable progression confirmed by pathology.3)Surgical removal of primary tumor with tumor present on final pathology.4)Salvage neck dissection >20 weeks after completion of CRT with tumor present on final pathology.5)Metastatic PD.DOR data censored on date of last adequate tumor assessment for subject with no overall response.All randomized with unconfirmed CR or PR.

End point type

Secondary

End point timeframe

From the first documentation of objective tumor response to the first documentation of PD or death or censored date, whichever occurred first (up to 37 months)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	259	260
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

End point description

Adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. TEAE was defined as event with onset dates occurring during the on-treatment period. Safety analysis set included all subjects who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline up to 44 months

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	348	344
Units: subjects
Grade 1	10	8
Grade 2	30	53
Grade 3	224	215
Grade 4	59	49
Grade 5	22	17

No statistical analyses for this end point

Secondary: Number of Subjects with Shift From Baseline in Clinical Laboratory Parameters

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End point title

Number of Subjects with Shift From Baseline in Clinical Laboratory Parameters

End point description

Grade 1 and 3 ranges: Anemia:Hb:<LLN-10.0,<8.0 g/dL;LC decreased (dec):<LLN-800/mm^3,500-200/mm^3;LC increased (inc):grade 3:>20,000/mm^3:NC dec:<LLN-1500/mm^3;<1000-500/mm^3;PC dec:<LLN-75,000/mm^3;<50,000-25,000/mm^3;WBC dec:<LLN-3000/mm^3;<2000-1000/mm^3;ALT inc:>ULN-3.0*ULN;>5.0-20.0*ULN;ALP & GGT inc:>ULN-2.5*ULN;>5.0-20.0*ULN;AST inc:>ULN-3.0*ULN;>5.0-20.0*ULN;BB inc:>ULN-1.5*ULN;>3.0-10.0*ULN;CH high:>ULN-300 mg/dL;>400-500 mg/dL;Hypercalcemia:>ULN-11.5;>12.5-13.5mg/dL;Hyperglycemia:>ULN-160; >250-500mg/dL;Hyperkalemia:>ULN-5.5;>6.0-7.0mmol/L;Hypermagnesemia:>ULN-3.0;>3.0-8.0 mg/dL;Hypernatremia:>ULN-150; >155-160 mmol/L;Hypertriglyceridemia;150-300;>500-1000 mg/dL;Hypoalbuminemia:<LLN-3;<2g/dL;Hypocalcemia:<LLN-8.0;<8.0-7.0mg/dL;Hypokalemia:<LLN-3.0;<3.0-2.5mmol/L;Hypomagnesemia;<LLN-1.2;<0.9-0.7 mg/dL;Hyponatremia:<LLN-130;<130-120mmol/L;Hypophosphatemia:<LLN-2.5;<2.0-1.0mg/dL. Safety. N=subjects evaluable for this endpoint, n=subjects evaluable for each specified category.

End point type

Secondary

End point timeframe

Baseline up to 15 months

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	346	340
Units: subjects
Anemia: New/worsened (N/W) grade >=1 (n =346,340)	314	311
Anemia: N/W to grade >=3 (n =346, 340)	42	49
LC Dec: N/W to grade >=1(n =346, 340)	336	330
LC Decreased: N/W to grade >=3(n =346, 340)	279	284
LC Increased: N/W to grade >=1(n =346, 340)	7	7
LC increased: N/W to grade >=3 (n =346, 340)	0	0
NC Decreased: N/W to grade >=1 (n =346, 340)	257	237
NC Decreased N/W to grade >=3 (n =346, 340)	120	101
PC Decreased : N/W to grade >=1 (n =346, 340)	157	154
PC Decreased: N/W to grade >=3 (n =346, 340)	20	7
WBC Decreased: N/W to grade >=1 (n =346, 340)	309	307
WBC Decreased: N/W to grade >=3 (n =346, 340)	121	129
ALT increased: N/W to grade >=1 (n =346, 340)	152	135
ALT increased: N/W to grade >=3 (n =346, 340)	13	2
ALP: N/W to grade >=1 (n =346, 340)	72	49
ALP increased: N/W to grade >=3 (n =346, 340)	1	1
AST increased: N/W to grade >=1 (n= 345, 340)	146	111
AST increased: N/W to grade >=3 (n =345, 340)	11	4
Bilurubin increased: N/W to grade >=1(n =346,340)	58	54
Bilirubin increased: N/W to grade >=3 (n=346, 340)	9	4
Cholesterol (CH) high:N/W to grade >=1(n=161,164)	25	21
CH high: N/W to grade >=3 (n=161,164)	0	0
CPK increased: N/W grade >=1 (n=160,156)	7	7
CPK increased: N/W to grade >=3 (n=160,156)	0	1
Creatinine increased: N/W to grade >=1 (n=346,340)	334	325
Creatinine increased: N/W to grade >=3 (n=346,340)	36	37
GGT increased: N/W to grade >=1 (n=191,193)	37	23
GGT increased: N/W to grade >=3 (n=191,193)	10	5
Hypercalcemia: N/W to grade >=1 (n=346,340)	67	59
Hypercalcemia: N/W to grade >=3 (n=346,340)	1	5
Hyperglycemia: N/W to grade >=1 (n=345,340)	144	137
Hyperglycemia: N/W to grade >=3 (n=345,340)	28	29
Hyperkalemia: N/W to grade >=1 (n=346,340)	106	113
Hyperkalemia: N/W to grade >=3 (n=346,340)	9	17
Hypermagnesemia: N/W to grade >=1 (n=346,339)	39	40
Hypermagnesemia: N/W to grade >=3 (n=346,339)	10	10
Hypernatremia: N/W to grade >=1 (n=346,340)	22	20
Hypernatremia: N/W to grade >=3 (n=346,340)	1	0
Hypertriglyceridemia: N/W to grade >=1 (n=162,161)	35	26
Hypertriglyceridemia: N/W to grade >=3 (n=162,161)	1	2
Hypoalbuminemia: N/W to grade >=1 (n=346,340)	195	170
Hypoalbuminemia: N/W to grade >=3 (n=346,340)	7	5
Hypocalcemia: N/W to grade >=1 (n=346,340)	82	88
Hypocalcemia: N/W to grade >=3(n=346,340)	8	14
Hypoglycemia: N/W to grade >=1 (n=345,340)	56	44
Hypoglycemia: N/W to grade >=3 (n=345,340)	2	2
Hypokalemia: N/W to grade >=1 (n=346,340)	140	122
Hypokalemia: N/W to grade >=3 (n=346,340)	55	49
Hypomagnesemia: N/W to grade >=1(n=346,339)	180	158
Hypomagnesemia: N/W to grade >=3(n=346,339)	8	12
Hyponatremia: N/W to grade >=1 (n=346,340)	232	212
Hyponatremia: N/W to grade >=3 (n=346,340)	74	70
Hypophosphatemia: N/W to grade >=1 (n=340,339)	108	100
Hypophosphatemia: N/W to grade >=3 (n=340,339)	21	19
Lipase increased: N/W to grade >=1 (n=161,154)	19	13
Lipase increased: N/W to grade >=3 (n=161,154)	11	3
Serum amylase increased: N/W Grade >=1 (n=159,152)	13	10
Serum amylase increased: N/W grade >=3 (n=159,152)	9	5

No statistical analyses for this end point

Secondary: Change From Baseline in Vital Sign - Systolic and Diastolic Blood Pressure

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End point title

Change From Baseline in Vital Sign - Systolic and Diastolic Blood Pressure

End point description

Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) measured in sitting position were reported. Safety analysis set included all subjects who received at least one dose of study drug. Here, "Overall Number of Subjects Analysed" signifies number of subjects evaluable for this endpoint and "n" signifies subjects evaluable for each specified category at each specified time point. Maintenance Phase =MP

End point type

Secondary

End point timeframe

Baseline, Lead-in phase: Day1; CRT Phase: Days 1, 8, 22, 25, 39, and 43; Maintenance phase: on Days 1 and 15 in Cycles 1 to 13 and EOT (3 days after the last dose of study drug)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	342	336
Units: millimeter of mercury
arithmetic mean (standard deviation)
DBP: Baseline (n=342, 336)	77.8 ± 10.13	78.1 ± 10.91
Lead in Phase: DBP: Change at Day 1 (n=2,2)	-3.0 ± 4.24	-8.0 ± 11.31
CRT Phase: DBP: Change at Day 1 (n=332,322)	-1.5 ± 9.52	-2.2 ± 9.91
CRT Phase: DBP: Change at Day 8 (n=323,315)	-3.8 ± 10.46	-3.9 ± 10.99
CRT Phase: DBP: Change at Day 22 (n-313,309)	-4.2 ± 11.77	-5.0 ± 10.95
CRT Phase: DBP: Change at Day 25 (n=310,306)	-3.4 ± 11.91	-3.3 ± 11.44
CRT Phase: DBP: Change at Day 39 (n=309,302)	-5.7 ± 11.83	-5.1 ± 12.14
CRT Phase: DBP: Change at Day 43 (n=293,283)	-5.0 ± 11.49	-4.7 ± 11.76
Maintenance Phase: DBP: Change at C1D1 (n=282,290)	-4.8 ± 11.43	-4.3 ± 11.67
MP: DBP: Change at C1D15 (n=265,279)	-3.7 ± 11.78	-4.0 ± 10.96
MP: DBP: Change at C2D1(n=266,277)	-3.3 ± 11.74	-3.3 ± 12.31
MP:DBP:Change at C2D15 (n=255,272)	-2.7 ± 11.05	-2.3 ± 11.82
MP:DBP: Change at C3D1(n=249,262)	-2.7 ± 11.37	-3.6 ± 11.42
MP: DBP: Change at C3D15 (n=234,255)	-2.7 ± 11.09	-3.4 ± 11.10
MP: DBP: Change at C4D1 (n=222,247)	-2.2 ± 12.07	-3.4 ± 11.42
MP: DBP: Change at C4D15(n=216,240)	-2.4 ± 11.38	-3.3 ± 11.54
MP: DBP: Change at C5D1(n=210,241)	-2.8 ± 11.61	-3.2 ± 10.88
MP: DBP: Change at C5D15(n=204,232)	-2.5 ± 11.89	-3.5 ± 10.69
MP: DBP: Change at C6D1(n=201,226)	-3.1 ± 11.21	-3.8 ± 11.28
MP: DBP: Change at C6D15(n=198,230)	-3.8 ± 12.20	-4.6 ± 11.43
MP: DBP: Change at C7D1(n=190,220)	-4.1 ± 11.48	-4.2 ± 11.52
MP: DBP: Change at C7D15 (n=185,214)	-3.8 ± 12.05	-3.8 ± 10.88
MP: DBP: Change at C8D1(n=173,209)	-2.9 ± 11.29	-4.1 ± 10.95
MP: DBP: Change at C8D15 (n=167,194)	-3.4 ± 11.48	-4.0 ± 12.29
MP: DBP: Change at C9D1(n=169,198)	-3.1 ± 11.78	-4.2 ± 10.98
MP: DBP: Change at C9D15(n=162,194)	-2.1 ± 11.52	-3.7 ± 12.07
MP: DBP: Change at C10D1 (n=161,192)	-2.2 ± 11.58	-3.5 ± 11.54
MP: DBP: Change at C10D15 (n=159,191)	-2.5 ± 10.90	-4.4 ± 11.69
MP: DBP: Change at C11D1(n=146,179)	-2.7 ± 11.01	-4.6 ± 11.23
MP: DBP: Change at C11D15(n=139,162)	-2.9 ± 10.37	-3.9 ± 10.22
MP: DBP: Change at C12D1(n=125,156)	-2.1 ± 9.51	-3.5 ± 11.40
MP: DBP: Change at C12D15(n=115,146)	-3.3 ± 11.78	-4.6 ± 11.19
MP: DBP: Change at C13D1(n=105,132)	-2.0 ± 9.60	-3.3 ± 11.49
MP: DBP: Change at C13D15(n=92,118)	-1.1 ± 10.22	-3.8 ± 11.44
DBP: EOT(n=225,210)	-2.4 ± 11.96	-3.2 ± 11.17
SBP: Baseline (n=342,336)	129.8 ± 16.42	130.5 ± 17.44
Lead in Phase:SBP: Change at Day 1(n=2,2)	-5.5 ± 2.12	12.5 ± 6.36
CRT Phase: SBP: Change at Day 1(n=332,322)	-2.5 ± 15.32	-3.5 ± 14.82
CRT Phase: SBP: Change at Day 8(n=323,315)	-8.3 ± 17.78	-8.0 ± 17.58
CRT Phase: SBP: Change at Day 22(n=313,309)	-8.9 ± 18.54	-8.4 ± 17.55
CRT Phase: SBP: Change at Day 25(n=310,306)	-7.9 ± 19.06	-5.8 ± 19.51
CRT Phase: SBP: Change at Day 39(n=309,302)	-10.6 ± 20.51	-10.3 ± 19.05
CRT Phase: SBP: Change at Day 43(n=293,283)	-9.6 ± 18.53	-9.2 ± 19.52
MP: SBP: Change at C1D1 (n=282,290)	-9.4 ± 17.97	-9.4 ± 20.19
MP: SBP: Change at C1D15(n=265, 279)	-9.5 ± 17.73	-8.2 ± 19.58
MP: SBP: Change at C2D1(n=266,277)	-7.0 ± 18.03	-7.8 ± 20.09
MP: SBP: Change at C2D15(n=255,272)	-7.9 ± 18.55	-6.6 ± 19.73
MP: SBP: Change at C3D1(n=249,262)	-7.3 ± 18.93	-8.5 ± 18.04
MP: SBP: Change at C3D15(n=234,255)	-8.3 ± 17.79	-7.1 ± 19.90
Maintenance Phase: SBP: Change at C4D1(n=222,247)	-8.4 ± 18.01	-8.9 ± 18.41
Maintenance Phase: SBP: Change at C4D15(n=216,240)	-6.2 ± 18.20	-8.2 ± 19.62
MP: SBP: Change at C5D1(n=210,241)	-7.6 ± 17.57	-7.7 ± 18.69
MP: SBP: Change at C5D15(n=204,232)	-8.4 ± 18.69	-7.5 ± 18.49
MP: SBP: Change at C6D1(n=201,206)	-7.6 ± 17.67	-8.3 ± 18.96
MP: SBP: Change at C6D15(n=198,230)	-7.1 ± 19.35	-9.4 ± 19.56
MP: SBP: Change at C7D1(n=190,220)	-9.0 ± 18.30	-8.9 ± 18.96
MP: SBP: Change at C7D15(n=185,214)	-8.7 ± 18.10	-6.8 ± 18.73
MP: SBP: Change at C8D1(n=173,209)	-6.5 ± 17.00	-9.4 ± 18.65
MP: SBP: Change at C8D15(n=167,194)	-6.8 ± 16.69	-7.9 ± 18.21
MP: SBP: Change at C9D1(n=169,198)	-6.1 ± 18.49	-8.1 ± 18.41
MP: SBP: Change at C9D15(n=162,194)	-6.3 ± 19.00	-6.7 ± 20.28
MP: SBP: Change at C10D1(n=161,192)	-6.1 ± 19.24	-7.2 ± 18.63
MP: SBP: Change at C10D15(n=159,191)	-5.6 ± 17.07	-7.7 ± 18.76
MP: SBP: Change at C11D1(n=146,179)	-6.3 ± 19.44	-7.7 ± 18.86
MP: SBP: Change at C11D15(n=139,162)	-6.3 ± 18.99	-7.4 ± 18.65
MP: SBP: Change at C12D1(n=125,156)	-6.8 ± 18.25	-6.1 ± 20.21
MP: SBP: Change at C12D15(n=115,146)	-7.1 ± 19.34	-7.8 ± 19.12
MP: SBP: Change at C13D1(n=105,132)	-5.8 ± 20.04	-6.2 ± 18.54
MP: SBP: Change at C13D15(n=92,118)	-4.9 ± 18.82	-5.6 ± 19.00
MP: SBP: EOT(n=225,210)	-7.0 ± 19.83	-4.9 ± 17.97

No statistical analyses for this end point

Secondary: Change From Baseline in Vital Sign - Pulse Rate

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End point title

Change From Baseline in Vital Sign - Pulse Rate

End point description

Change from baseline in pulse rate in sitting position in beats per minute was reported. Here, "Overall Number of Subjects Analysed" signifies number of subjects evaluable for this endpoint and "n" signifies subjects evaluable for each specified category at each specified time point.

End point type

Secondary

End point timeframe

Baseline, Lead-in phase: Day1; CRT Phase: Days 1, 8, 22, 25, 39, and 43; Maintenance phase: on Days 1 and 15 in Cycles 1 to 13 and EOT (3 days after the last dose of study drug)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	342	336
Units: beats per minute
arithmetic mean (standard deviation)
Baseline (n=342,336)	79.9 ± 13.72	86.0 ± 43.0
Lead in Phase: Change at Day 1 ((n=2,2)	-3.5 ± 0.71	-8.5 ± 19.09
CRT Phase: Change at Day 1 (n=331,322)	0.7 ± 11.70	1.3 ± 10.92
CRT Phase: Change at Day 8 (n=323,315)	1.5 ± 13.15	2.2 ± 12.42
CRT Phase: Change at Day 22(n=314,309)	0.5 ± 13.86	2.6 ± 12.24
CRT Phase: Change at Day 25(n=310,306)	-1.6 ± 14.87	-1.2 ± 13.90
CRT Phase: Change at Day 29(n=10,8)	-11.0 ± 20.47	3.6 ± 21.29
CRT Phase: Change at Day 39(n=310,301)	4.0 ± 15.46	4.3 ± 14.71
CRT Phase: Change at Day 43(n=293,283)	4.7 ± 16.82	6.1 ± 14.78
Maintenance Phase: Change at C1D1 1(n=282,291)	5.1 ± 16.23	7.5 ± 14.43
Maintenance Phase: Change at C1D15(n=265,279)	3.8 ± 15.04	6.3 ± 13.65
Maintenance Phase: Change at C2D1(n=266,277)	3.5 ± 15.30	5.9 ± 14.74
Maintenance Phase: Change at C2D15(n=254,272)	4.1 ± 15.32	4.9 ± 13.94
Maintenance Phase: Change at C3D1(n=249,262)	3.5 ± 14.49	3.9 ± 14.37
Maintenance Phase: Change at C3D15(n=234,255)	2.8 ± 14.73	2.8 ± 14.14
Maintenance Phase: Change at C4D1(n=222,247)	1.8 ± 14.79	3.8 ± 14.95
MP: Change at C4D15(n=216,240)	1.6 ± 14.80	3.8 ± 15.02
MP: Change at C5D1(n=210,241)	2.6 ± 13.88	2.9 ± 14.82
MP: Change at C5D15(n=204,232)	1.6 ± 15.11	3.3 ± 13.74
MP: Change at C6D1(n=201,226)	1.6 ± 15.42	2.7 ± 15.72
MP: Change at C6D15(n=198,230)	0.4 ± 14.04	1.4 ± 13.66
MP: Change at C7D1(n=190,220)	-0.1 ± 14.47	2.5 ± 14.18
MP: Change at C7D15(n=185,214)	-0.1 ± 14.24	1.4 ± 14.33
MP: Change at C8D1(n=173,209)	-0.2 ± 13.84	1.0 ± 13.67
MP: Change at C8D15(n=167,194)	-1.5 ± 14.52	1.5 ± 14.86
MP: Change at C9D1(n=169,198)	-1.0 ± 14.29	-0.1 ± 14.06
MP: Change at C9D15(n=162,194)	-1.0 ± 14.20	0.2 ± 14.44
MP: Change at C10D1(n=161,192)	-0.9 ± 13.40	0.7 ± 14.52
MP: Change at C10D15(n=159,191)	-0.5 ± 15.33	0.7 ± 14.66
MP: Change at C11D1(n=145,178)	-1.6 ± 14.57	0.2 ± 14.01
MP: Change at C11D15(n=139,162)	-0.2 ± 13.23	0.3 ± 12.93
MP: Change at C12D1(n=125,156)	-0.3 ± 13.92	0.4 ± 13.67
MP: Change at C12D15(n=115,146)	-1.4 ± 14.92	-0.5 ± 12.47
MP: Change at C13D1(n=105,132)	-1.4 ± 14.09	-0.1 ± 12.22
MP: Change at C13D15(n=92,118)	-1.3 ± 15.57	0.4 ± 13.24
EOT(n=223,210)	0.2 ± 14.73	1.9 ± 14.09

No statistical analyses for this end point

Secondary: Change from Baseline in the European Quality of Life- 5 Dimension-5 Levels (EQ-5D-5L) Index Score at CRT Phase and Maintenance Phase

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End point title

Change from Baseline in the European Quality of Life- 5 Dimension-5 Levels (EQ-5D-5L) Index Score at CRT Phase and Maintenance Phase

End point description

EQ-5D-5L is a standardized subject completed questionnaire that measures health status in terms of a single index value or utility score. EQ-5D-5L consisted of two components: a health state profile (descriptive system) and a visual analogue scale (VAS) in which subjects rate their overall health status from 0 (worst imaginable) to 100 (best imaginable), where higher scores indicated better health status. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. EQ-5D-5L health status index score range between 0 to 1. Higher score indicated better health status. FAS included all randomized subjects. Overall Number of Subjects Analysed=subjects evaluable for this endpoint and "n" signifies subjects evaluable for each specified category at each specified time point.

End point type

Secondary

End point timeframe

Baseline, CRT Phase: Days 1 and 29; Maintenance phase: Cycle 1/Day 1, Cycle 3/Day 1, Cycle 7/Day 1, Cycle 7/Day 15, Cycle 11/Day 1, Cycle 11/Day 15, EOT (3 days after the last dose of study drug)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	334	333
Units: units on a scale
arithmetic mean (standard deviation)
Baseline: (n=334, 333)	0.7718 ± 0.17822	0.7615 ± 0.18517
CRT Phase: Change at Day 1: (n=321, 318)	-0.0078 ± 0.13269	0.0176 ± 0.14066
CRT Phase: Change at Day 2 (n=293, 276)	-0.0915 ± 0.22053	-0.0487 ± 0.19175
MP: Change at C1D1 (n=272, 279)	-0.0749 ± 0.22126	-0.0519 ± 0.17253
MP: Change at C3D1 (n=239, 243)	-0.0203 ± 0.21340	-0.0160 ± 0.18179
MP: Change at C7D1 (n=95,113)	0.0088 ± 0.16690	0.0140 ± 0.16240
MP: Change at C7D15 (n=59, 79)	0.0552 ± 0.18544	0.0472 ± 0.17990
MP: Change at C11D1 (n=90,111)	0.0376 ± 0.21078	0.0792 ± 0.19287
MP: Change at C11D15 (n=36, 40)	0.0673 ± 0.17227	0.0389 ± 0.18732
MP: Change at EOT (n=184,187)	-0.0051 ± 0.24528	0.0074 ± 0.24874

No statistical analyses for this end point

Secondary: Change From Baseline in the European Quality of Life- 5 Dimension-5 Levels (EQ-5D-5L) VAS Score at CRT Phase and Maintenance Phase

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End point title

Change From Baseline in the European Quality of Life- 5 Dimension-5 Levels (EQ-5D-5L) VAS Score at CRT Phase and Maintenance Phase

End point description

EQ-5D-5L is a standardized subject completed questionnaire that measures health status in terms of a single index value or utility score. EQ-5D-5L consisted of two components: a health state profile (descriptive system) and a visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. EQ-5D-5L health status index score range between 0 to 1. Higher score indicated worse health status. In VAS subjects rate their overall health status from 0 (worst imaginable) to 100 (best imaginable), where higher scores indicated better health status. FAS included all randomized subjects. "Overall Number of subjects Analysed" signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable at each specified time point.

End point type

Secondary

End point timeframe

Baseline, CRT Phase: Days 1 and 29; Maintenance phase: Cycle 1/Day 1, Cycle 3/Day 1, Cycle 7/Day 1, Cycle 7/Day 15, Cycle 11/Day 1, Cycle 11/Day 15, EOT (3 days after the last dose of study drug)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	333	330
Units: units on a scale
arithmetic mean (standard deviation)
Baseline: (n=333, 330)	75.8 ± 18.20	74.9 ± 18.24
CRT Phase: Change at Day 1 (n=317, 314)	-1.1 ± 13.49	-1.4 ± 11.39
CRT Phase: Change at Day 29 (n=291, 271)	-10.9 ± 19.94	-9.2 ± 18.70
MP: Change at C1D1 (n=272, 277)	-7.7 ± 19.05	-6.2 ± 18.67
MP: Change at C3D1 (n=240, 236)	-1.8 ± 18.00	-0.7 ± 16.14
MP: Change at C7D1 (n=95,113)	-0.6 ± 14.91	8.6 ± 81.42
MP: Change at C7D15 (n=59, 78)	4.8 ± 18.52	3.1 ± 19.28
MP: Change at C11D1 (n=89,108)	0.3 ± 17.60	4.3 ± 16.10
MP: Change at C11D15 (n=37, 40)	10.1 ± 24.69	2.4 ± 18.20
MP: Change at EOT (n=183, 184)	-1.9 ± 22.55	0.7 ± 19.28

No statistical analyses for this end point

Secondary: Change From Baseline in National Cancer Comprehensive Network Head and Neck Symptom Index-22 Item Scores (NCCN FHNSI-22) at CRT Phase and Maintenance Phase

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End point title

Change From Baseline in National Cancer Comprehensive Network Head and Neck Symptom Index-22 Item Scores (NCCN FHNSI-22) at CRT Phase and Maintenance Phase

End point description

The NCCN FHNSI-22 questionnaire measured disease symptoms, treatment side effects and overall quality of life in participants with head and neck cancer. The questionnaire contained 22 items with 5-point Likert scales ranging from 0 to 4 as follows: ‘not at all = 0’, a little bit = 1, somewhat = 2, quite a bit = 3 and very much = 4. Total score ranged from 0 to 88 where, higher scores represented better symptomatology, quality of life or functioning. FAS included all randomized subjects. Here, "Overall Number of Subjects Analysed" signifies number of subjects evaluable for this endpoint and "n" signifies subjects evaluable for each specified category at each specified time point.

End point type

Secondary

End point timeframe

Baseline, CRT Phase: Days 1 and 29; Maintenance phase: Cycle 1/Day 1, Cycle 3/Day 1, Cycle 7/Day 1, Cycle 7/Day 15, Cycle 11/Day 1, Cycle 11/Day 15, EOT (3 days after the last dose of study drug)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	333	331
Units: units on a scale
arithmetic mean (standard deviation)
Baseline: (n=333, 331)	60.56 ± 13.731	61.05 ± 13.155
CRT Phase: Change at Day 1: (n=318, 317)	-0.59 ± 8.719	-0.14 ± 9.136
CRT Phase: Change at Day 29 (n=294, 275)	-14.34 ± 16.847	-14.56 ± 15.470
MP: Change at C1D1 (n=272, 281)	-11.33 ± 16.054	-12.08 ± 14.950
MP: Change at C3D1 (n=241, 241)	-3.81 ± 14.017	-2.26 ± 13.625
MP: Change at C7D1 (n=96,113)	-0.86 ± 12.503	-0.51 ± 14.585
MP: Change at C7D15 (n=61, 78)	3.96 ± 14.035	0.92 ± 14.454
MP: Change at C11D1 (n=88,110)	2.68 ± 13.367	4.90 ± 14.207
MP: Change at C11D15 (n=37, 40)	3.96 ± 14.322	3.37 ± 12.689
MP: Change at EOT (n=184, 187)	-2.35 ± 17.428	0.79 ± 16.509

No statistical analyses for this end point

Secondary: Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)

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End point title

Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)

End point description

PD-L1 biomarker expression in tumor tissue as assessed by IHC in the form of positive immune cells and tumor staining cells. Biomarker analysis set was a subset of the safety analysis set included subjects who had at least one screening biomarker assessment. Here, "Overall Number of Subjects Analysed" signifies number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline (prior to first dose)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	299	307
Units: % of PD-L1+ cells
arithmetic mean (standard deviation)
Positive Immune Cells	7.4 ± 7.06	8.3 ± 8.47
Tumor Staining Cells	12.7 ± 24.90	18.3 ± 31.12

No statistical analyses for this end point

Secondary: Mean Percentage (%) of Total Tumor Area Occupied by Cluster of Differentiation 8 (CD8+) Cells

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End point title

Mean Percentage (%) of Total Tumor Area Occupied by Cluster of Differentiation 8 (CD8+) Cells

End point description

Description: CD8+ cells are the type of T-lymphocytes. Mean percentage of total tumor area occupied by CD8+ Cells has been reported. Area was measured in millimeter square (mm^2). Biomarker analysis set was a subset of the safety analysis set included subjects who had at least one screening biomarker assessment. Here, "Overall Number of Subjects Analysed" signifies number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline (prior to first dose)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	289	294
Units: % of tumor area occupied by CD8+ cells
arithmetic mean (standard deviation)	4.9 ± 6.03	5.8 ± 6.55

No statistical analyses for this end point

Secondary: Percentage of Subjects With Positive and Negative Pathology of Neck Dissection

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End point title

Percentage of Subjects With Positive and Negative Pathology of Neck Dissection

End point description

Percentage of subjects with positive and negative pathology of neck dissection were reported. Positive pathology included live tumor cells present or 10% or greater vital tumor tissues. Negative pathology included no live tumor cells present, complete tumor regression, no evidence of vital tumor tissues, less than 10% vital tumor tissue, or not consistent with disease under study. Analysis population included all subjects who had received at least one dose of study drug and who had salvage neck dissection.

End point type

Secondary

End point timeframe

From randomization until PD as per investigator assessment (up to 37 months)

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	14	15
Units: percentage of subjects
number (not applicable)
Negative Pathology	7.14	26.70
Positive pathology	71.43	40.00
Pathology not reported	21.43	33.30

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) of Avelumab

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End point title

Maximum Plasma Concentration (Cmax) of Avelumab ^[6]

End point description

Maximum observed plasma concentration (Cmax) of Avelumab is reported. PK concentration analysis was a subset of the safety analysis set and included subjects who had at least one post-dose concentration measurement above the lower limit of quantitation (LLQ) for avelumab or cisplatin. Here’ 'overall number of subjects analysed' signifies subjects evaluable for this endpoint and ‘n’ signifies subjects evaluable at specified time point.

End point type

Secondary

End point timeframe

Pre-dose and end of infusion on Day 1 of lead-in phase, Days 8, 25 of CRT phase, Day 1 of Cycle 1 and 2 (each cycle 28 days)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analyzed for the arms specified

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)
Number of subjects analysed	236
Units: nanogram per milliliter
geometric mean (geometric coefficient of variation)
Lead-in/Day 1 (n= 236)	203.6 ± 31
CRT/Day 8 (n= 207)	190.9 ± 66
CRT/Day 25 (n= 189)	162.4 ± 114
Cycle 1 Day 1 (n= 152)	142 ± 117
Cycle 2 Day 1 (n= 128)	154.9 ± 97

No statistical analyses for this end point

Secondary: Predose Plasma Concentration (Ctrough) of Avelumab

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End point title

Predose Plasma Concentration (Ctrough) of Avelumab ^[7]

End point description

Ctrough refers to plasma concentration of Avelumab observed just before treatment administration. PK concentration analysis was a subset of the safety analysis set and included subjects who had at least one post-dose concentration measurement above the lower limit of quantitation (LLQ) for avelumab or cisplatin. Here’ 'overall number of subjects analysed' signifies subjects evaluable for this endpoint and ‘n’ signifies subjects evaluable at specified time point.

End point type

Secondary

End point timeframe

Pre-dose on Day 1 of lead-in phase, Days 8, 25 of CRT phase, Day 1 of Cycle 1, 2, 5, 8, 11 (each cycle 28 days)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analyzed for the arms specified

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)
Number of subjects analysed	267
Units: microgram per milliliter
geometric mean (geometric coefficient of variation)
Lead-in/Day 1 (n =263)	2.988 ± 1590
CRT/Day 8 (n =267)	11.9 ± 63
CRT/Day 25 (n =251)	6.284 ± 138
Cycle 1/Day 1 (n =183)	2.354 ± 131
Cycle 2/Day 1 (n =198)	17.56 ± 70
Cycle 5/Day 1 (n =147)	24.35 ± 66
Cycle 8/Day 1 (n =125)	29.59 ± 69
Cycle 11/Day 1 (n =113)	30.85 ± 79

No statistical analyses for this end point

Secondary: Dose Normalized Maximum Plasma Concentration (Cmax [dn]) of Total and Free Cisplastin

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End point title

Dose Normalized Maximum Plasma Concentration (Cmax [dn]) of Total and Free Cisplastin

End point description

Dose normalized (dn) Cmax was calculated by dividing Cmax by the exact dose of total or free Cisplastin (in mg) administered to a subject. PK concentration analysis was a subset of the safety analysis set and included subjects who had at least one post-dose concentration measurement above the lower limit of quantitation (LLQ) for avelumab or cisplatin. Here’ 'overall number of subjects analysed' signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	12	23
Units: nanogram per milliliter per milligram
geometric mean (geometric coefficient of variation)
Total Cisplastin	26.23 ± 36	25.33 ± 26
Free Cisplastin	11.84 ± 29	7.286 ± 96

No statistical analyses for this end point

Secondary: Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) of Total and Free Cisplatin

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End point title

Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) of Total and Free Cisplatin

End point description

Area under the plasma concentration time-curve from time zero to the time of last measured concentration (AUClast). AUClast (dn) was calculated by dividing AUClast by the exact dose of cisplastin (in mg) administered to a subject. PK concentration analysis was a subset of the safety analysis set and included subjects who had at least one post-dose concentration measurement above the lower limit of quantitation (LLQ) for avelumab or cisplatin. Here, 'overall number of subjects analysed' signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	10	20
Units: nanogram*hour/milliliter/milligram
geometric mean (geometric coefficient of variation)
Total Cisplatin	299.1 ± 30	332.7 ± 17
Free Cisplatin	36.53 ± 51	29.08 ± 49

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) of Total and Free Cisplatin

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End point title

Maximum Plasma Concentration (Cmax) of Total and Free Cisplatin

End point description

Maximum observed plasma concentration (Cmax) of total and free Cisplatin is reported. PK concentration analysis was a subset of the safety analysis set and included subjects who had at least one post-dose concentration measurement above the lower limit of quantitation (LLQ) for avelumab or cisplatin. Here’ 'overall number of subjects analysed' signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	12	23
Units: nanogram per milliliter
geometric mean (geometric coefficient of variation)
Total Cisplastin	3781 ± 44	4001 ± 34
Free Cisplastin	1710 ± 53	1151 ± 109

No statistical analyses for this end point

Secondary: Time to Attain Maximum Observed Plasma Concentration (Tmax) of Total and Free Cisplatin

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End point title

Time to Attain Maximum Observed Plasma Concentration (Tmax) of Total and Free Cisplatin

End point description

Time to reach maximum observed plasma concentration (Tmax) of total and free Cisplatin. PK concentration analysis was a subset of the safety analysis set and included subjects who had at least one post-dose concentration measurement above the lower limit of quantitation (LLQ) for avelumab or cisplatin. Here’ 'overall number of subjects analysed' signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose, mid-infusion, end of infusion, 3, 4, and 24 hours post dose on Day 1 of CRT phase

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	12	23
Units: hour
median (full range (min-max))
Total Cisplastin	1.000 (0.500 to 2.40)	1.170 (0.983 to 24.0)
Free Cisplastin	1.000 (0.500 to 1.17)	1.000 (0.500 to 2.12)

No statistical analyses for this end point

Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

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End point title

Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status ^[8]

End point description

ADA never-positive was defined as no positive ADA results at any time point; ADA-negative subjects (titer less than< cut point) and ADA ever-positive was defined as at least one positive ADA result at any time point; ADA-positive subjects (titer greater than or equal to cut point). Immunogenicity analysis set was a subset of the safety analysis set which included subjects who had at least 1 ADA/nAb sample collected for avelumab in Avelumab + Standard of Care Chemotherapy (SOC CRT) arm.

End point type

Secondary

End point timeframe

pre-dose on Day 1 up to 30 Days after the end of treatment

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to be analyzed for the arms specified

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)
Number of subjects analysed	331
Units: subjects
ADA never-positive	277
ADA ever-positive	54

No statistical analyses for this end point

Secondary: Number of Subjects With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status

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End point title

Number of Subjects With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status

End point description

End point type

Secondary

End point timeframe

Day 1 of lead-in phase and on Days 8 and 25 of CRT phase

End point values	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Number of subjects analysed	0 ^[9]	0 ^[10]
Units: subjects

Notes
[9] - Due to study termination and program decision data for nAb was not collected and analyzed.
[10] - Due to study termination and program decision data for nAb was not collected and analyzed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 44 months

Adverse event reporting additional description

Same event may appear as AE, serious AE, here distinct events are presented. Event may be serious in 1 participant and non-serious in another or 1 subject may have experienced both serious, non-serious event. Safety analysis set evaluated.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Avelumab + Standard of Care Chemotherapy (SOC CRT)

Reporting group description

Participants with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) were administered with avelumab 10 milligram per kilogram (mg/kg) intravenous (IV) injection on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase participants also received SOC CRT: cisplatin 100 milligram per square meter (mg/m^2) on Days 1, 22, 43 and intensity-modulated radiation therapy (IMRT) 5 days a week. CRT phase was followed by maintenance phase (12 months) in which participants received avelumab 10 mg/kg IV injection every 2 weeks. All participants were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose participants were followed up on Day 90 via telephone call thereafter in long term (LT) follow up period every 16 weeks for survival and new systemic anticancer treatment.

Reporting group title

Placebo + SOC CRT

Reporting group description

Participants with LA SCCHN were administered with placebo IV injection matched to avelumab on Day 1 of the Lead-in Phase (7 days) and on Days 8, 25 and 39 in CRT phase (63 days). In CRT phase participants also received SOC CRT: cisplatin mg/m^2 on Days 1, 22 and 43 + IMRT 5 days a week. CRT phase was followed by maintenance phase (12 months) in which participants received placebo IV injection every 2 weeks. All participants were followed for safety 30 days after the last study treatment administration or until the time of initiation of new systemic anticancer treatment. If any concern arose participants were followed up on Day 90 via telephone call thereafter in long term follow up period every 16 weeks for survival and new systemic anticancer treatment.

Serious adverse events	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Total subjects affected by serious adverse events
subjects affected / exposed	184 / 348 (52.87%)	177 / 344 (51.45%)
number of deaths (all causes)	86	62
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal neoplasm
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transitional cell cancer of the renal pelvis and ureter
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Plasmacytoma
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	4 / 348 (1.15%)	4 / 344 (1.16%)
occurrences causally related to treatment / all	0 / 4	1 / 5
deaths causally related to treatment / all	0 / 2	0 / 3
Vascular disorders
Capillary leak syndrome
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Embolism
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 0
Lymphorrhoea
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	2 / 348 (0.57%)	4 / 344 (1.16%)
occurrences causally related to treatment / all	1 / 2	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Shock
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Phlebitis superficial
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular rupture
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Vasculitis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venous haemorrhage
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Surgical and medical procedures
Gastrostomy
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 348 (0.57%)	6 / 344 (1.74%)
occurrences causally related to treatment / all	2 / 2	5 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	2 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chills
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Condition aggravated
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Death
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	1 / 2	0 / 2
Fatigue
subjects affected / exposed	2 / 348 (0.57%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	1 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 348 (0.29%)	6 / 344 (1.74%)
occurrences causally related to treatment / all	1 / 1	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperpyrexia
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 348 (0.00%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypothermia
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ill-defined disorder
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	5 / 348 (1.44%)	6 / 344 (1.74%)
occurrences causally related to treatment / all	6 / 6	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 348 (0.00%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	12 / 348 (3.45%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	5 / 15	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Swelling
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Scrotal oedema
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 2	1 / 1
Asphyxia
subjects affected / exposed	1 / 348 (0.29%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1
Aspiration
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Atelectasis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	5 / 348 (1.44%)	7 / 344 (2.03%)
occurrences causally related to treatment / all	1 / 5	3 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	2 / 348 (0.57%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	0 / 2	1 / 4
deaths causally related to treatment / all	0 / 1	0 / 1
Hypoxia
subjects affected / exposed	1 / 348 (0.29%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal haemorrhage
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal inflammation
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal oedema
subjects affected / exposed	5 / 348 (1.44%)	4 / 344 (1.16%)
occurrences causally related to treatment / all	7 / 7	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Laryngeal necrosis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal stenosis
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Obstructive airways disorder
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oropharyngeal pain
subjects affected / exposed	1 / 348 (0.29%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal haemorrhage
subjects affected / exposed	2 / 348 (0.57%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	1 / 2	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 1
Pharyngeal inflammation
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal necrosis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal oedema
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal stenosis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal ulceration
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	5 / 348 (1.44%)	5 / 344 (1.45%)
occurrences causally related to treatment / all	1 / 5	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Pneumonitis
subjects affected / exposed	6 / 348 (1.72%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	5 / 6	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Pneumothorax
subjects affected / exposed	1 / 348 (0.29%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Productive cough
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory distress
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	2 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 348 (0.00%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 2
Respiratory tract oedema
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stridor
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillar haemorrhage
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Tracheal stenosis
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	3 / 348 (0.86%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device malfunction
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	1 / 348 (0.29%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Embedded device
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	7 / 348 (2.01%)	6 / 344 (1.74%)
occurrences causally related to treatment / all	6 / 7	6 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eastern Cooperative Oncology Group performance status worsened
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Hepatic enzyme increased
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphocyte count decreased
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	4 / 348 (1.15%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	5 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	6 / 348 (1.72%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	4 / 6	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrostomy failure
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nerve injury
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic injury
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural fever
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation associated pain
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation fibrosis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation injury
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation mucositis
subjects affected / exposed	0 / 348 (0.00%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation necrosis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation skin injury
subjects affected / exposed	3 / 348 (0.86%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	6 / 6	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Stoma site inflammation
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stoma site pain
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheal obstruction
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheal haemorrhage
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoradionecrosis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 348 (0.29%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Cardiac failure
subjects affected / exposed	1 / 348 (0.29%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	1 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Cardiac failure congestive
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Brain hypoxia
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Coma
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subacute combined cord degeneration
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	8 / 348 (2.30%)	12 / 344 (3.49%)
occurrences causally related to treatment / all	7 / 9	10 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	9 / 348 (2.59%)	5 / 344 (1.45%)
occurrences causally related to treatment / all	9 / 9	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	5 / 348 (1.44%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	5 / 5	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic haematoma
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tinnitus
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Pterygium
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 348 (0.00%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 348 (0.29%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 348 (0.29%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dry mouth
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer perforation
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	15 / 348 (4.31%)	13 / 344 (3.78%)
occurrences causally related to treatment / all	13 / 19	11 / 14
deaths causally related to treatment / all	0 / 0	0 / 1
Faecaloma
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Haematemesis
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Haematochezia
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	2 / 348 (0.57%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth swelling
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	7 / 348 (2.01%)	9 / 344 (2.62%)
occurrences causally related to treatment / all	9 / 9	10 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Odynophagia
subjects affected / exposed	3 / 348 (0.86%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	2 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal obstruction
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oral pain
subjects affected / exposed	1 / 348 (0.29%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Salivary hypersecretion
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	7 / 348 (2.01%)	4 / 344 (1.16%)
occurrences causally related to treatment / all	10 / 10	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Tongue ulceration
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tongue haemorrhage
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	11 / 348 (3.16%)	13 / 344 (3.78%)
occurrences causally related to treatment / all	14 / 14	12 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Erythema multiforme
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	12 / 348 (3.45%)	11 / 344 (3.20%)
occurrences causally related to treatment / all	11 / 12	11 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephritis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oliguria
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal disorder
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 348 (0.00%)	4 / 344 (1.16%)
occurrences causally related to treatment / all	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adrenal insufficiency
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma muscle
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neck pain
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oligoarthritis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess oral
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis bacterial
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida infection
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 348 (0.86%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	2 / 4	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis candida
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Epididymitis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epiglottitis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 348 (0.29%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	2 / 348 (0.57%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection bacterial
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic infection
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Parotitis
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oral infection
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 348 (0.00%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	25 / 348 (7.18%)	20 / 344 (5.81%)
occurrences causally related to treatment / all	8 / 30	8 / 21
deaths causally related to treatment / all	0 / 1	0 / 2
Pneumonia bacterial
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Respiratory tract infection
subjects affected / exposed	4 / 348 (1.15%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	7 / 348 (2.01%)	5 / 344 (1.45%)
occurrences causally related to treatment / all	3 / 9	3 / 5
deaths causally related to treatment / all	1 / 2	0 / 0
Sinusitis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stoma site abscess
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stoma site infection
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Adult failure to thrive
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cachexia
subjects affected / exposed	2 / 348 (0.57%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 1
Decreased appetite
subjects affected / exposed	5 / 348 (1.44%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	7 / 7	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	9 / 348 (2.59%)	15 / 344 (4.36%)
occurrences causally related to treatment / all	7 / 10	9 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1
Failure to thrive
subjects affected / exposed	2 / 348 (0.57%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 348 (0.29%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 348 (0.57%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemic hyperosmolar nonketotic syndrome
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 348 (0.00%)	2 / 344 (0.58%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	4 / 348 (1.15%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	4 / 4	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	4 / 348 (1.15%)	7 / 344 (2.03%)
occurrences causally related to treatment / all	3 / 4	6 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	1 / 348 (0.29%)	0 / 344 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ketoacidosis
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	2 / 348 (0.57%)	3 / 344 (0.87%)
occurrences causally related to treatment / all	0 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic disorder
subjects affected / exposed	0 / 348 (0.00%)	1 / 344 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Avelumab + Standard of Care Chemotherapy (SOC CRT)	Placebo + SOC CRT
Total subjects affected by non serious adverse events
subjects affected / exposed	344 / 348 (98.85%)	340 / 344 (98.84%)
Vascular disorders
Hypertension
subjects affected / exposed	32 / 348 (9.20%)	28 / 344 (8.14%)
occurrences all number	63	54
Hypotension
subjects affected / exposed	22 / 348 (6.32%)	14 / 344 (4.07%)
occurrences all number	26	16
Lymphoedema
subjects affected / exposed	18 / 348 (5.17%)	15 / 344 (4.36%)
occurrences all number	19	17
General disorders and administration site conditions
Chills
subjects affected / exposed	39 / 348 (11.21%)	7 / 344 (2.03%)
occurrences all number	43	8
Asthenia
subjects affected / exposed	63 / 348 (18.10%)	58 / 344 (16.86%)
occurrences all number	124	102
Fatigue
subjects affected / exposed	116 / 348 (33.33%)	127 / 344 (36.92%)
occurrences all number	227	232
Localised oedema
subjects affected / exposed	22 / 348 (6.32%)	20 / 344 (5.81%)
occurrences all number	24	25
Malaise
subjects affected / exposed	20 / 348 (5.75%)	23 / 344 (6.69%)
occurrences all number	39	39
Mucosal inflammation
subjects affected / exposed	146 / 348 (41.95%)	131 / 344 (38.08%)
occurrences all number	333	289
Oedema peripheral
subjects affected / exposed	19 / 348 (5.46%)	16 / 344 (4.65%)
occurrences all number	27	23
Pyrexia
subjects affected / exposed	87 / 348 (25.00%)	45 / 344 (13.08%)
occurrences all number	140	69
Pain
subjects affected / exposed	23 / 348 (6.61%)	28 / 344 (8.14%)
occurrences all number	26	41
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	74 / 348 (21.26%)	63 / 344 (18.31%)
occurrences all number	96	85
Dysphonia
subjects affected / exposed	51 / 348 (14.66%)	47 / 344 (13.66%)
occurrences all number	64	78
Dyspnoea
subjects affected / exposed	33 / 348 (9.48%)	33 / 344 (9.59%)
occurrences all number	39	36
Hiccups
subjects affected / exposed	26 / 348 (7.47%)	23 / 344 (6.69%)
occurrences all number	33	32
Pharyngeal inflammation
subjects affected / exposed	24 / 348 (6.90%)	23 / 344 (6.69%)
occurrences all number	48	35
Oropharyngeal pain
subjects affected / exposed	75 / 348 (21.55%)	92 / 344 (26.74%)
occurrences all number	131	150
Productive cough
subjects affected / exposed	40 / 348 (11.49%)	31 / 344 (9.01%)
occurrences all number	53	37
Psychiatric disorders
Anxiety
subjects affected / exposed	26 / 348 (7.47%)	34 / 344 (9.88%)
occurrences all number	27	42
Insomnia
subjects affected / exposed	57 / 348 (16.38%)	47 / 344 (13.66%)
occurrences all number	67	56
Depression
subjects affected / exposed	10 / 348 (2.87%)	18 / 344 (5.23%)
occurrences all number	10	21
Investigations
Alanine aminotransferase increased
subjects affected / exposed	56 / 348 (16.09%)	30 / 344 (8.72%)
occurrences all number	92	43
Aspartate aminotransferase increased
subjects affected / exposed	55 / 348 (15.80%)	26 / 344 (7.56%)
occurrences all number	87	39
Amylase increased
subjects affected / exposed	22 / 348 (6.32%)	10 / 344 (2.91%)
occurrences all number	41	11
Blood creatinine increased
subjects affected / exposed	88 / 348 (25.29%)	73 / 344 (21.22%)
occurrences all number	196	167
Blood alkaline phosphatase increased
subjects affected / exposed	22 / 348 (6.32%)	9 / 344 (2.62%)
occurrences all number	36	21
Blood urea increased
subjects affected / exposed	18 / 348 (5.17%)	17 / 344 (4.94%)
occurrences all number	26	33
Gamma-glutamyltransferase increased
subjects affected / exposed	23 / 348 (6.61%)	15 / 344 (4.36%)
occurrences all number	49	24
Lymphocyte count decreased
subjects affected / exposed	40 / 348 (11.49%)	42 / 344 (12.21%)
occurrences all number	153	204
Neutrophil count decreased
subjects affected / exposed	64 / 348 (18.39%)	60 / 344 (17.44%)
occurrences all number	115	117
Weight decreased
subjects affected / exposed	157 / 348 (45.11%)	171 / 344 (49.71%)
occurrences all number	282	333
Platelet count decreased
subjects affected / exposed	40 / 348 (11.49%)	33 / 344 (9.59%)
occurrences all number	66	75
White blood cell count decreased
subjects affected / exposed	69 / 348 (19.83%)	64 / 344 (18.60%)
occurrences all number	164	203
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	24 / 348 (6.90%)	6 / 344 (1.74%)
occurrences all number	40	18
Radiation skin injury
subjects affected / exposed	135 / 348 (38.79%)	136 / 344 (39.53%)
occurrences all number	216	223
Nervous system disorders
Dizziness
subjects affected / exposed	41 / 348 (11.78%)	33 / 344 (9.59%)
occurrences all number	45	40
Dysgeusia
subjects affected / exposed	106 / 348 (30.46%)	119 / 344 (34.59%)
occurrences all number	154	166
Neuropathy peripheral
subjects affected / exposed	11 / 348 (3.16%)	28 / 344 (8.14%)
occurrences all number	12	45
Headache
subjects affected / exposed	44 / 348 (12.64%)	41 / 344 (11.92%)
occurrences all number	55	54
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	64 / 348 (18.39%)	46 / 344 (13.37%)
occurrences all number	172	123
Anaemia
subjects affected / exposed	206 / 348 (59.20%)	192 / 344 (55.81%)
occurrences all number	531	490
Neutropenia
subjects affected / exposed	102 / 348 (29.31%)	98 / 344 (28.49%)
occurrences all number	192	169
Lymphopenia
subjects affected / exposed	33 / 348 (9.48%)	27 / 344 (7.85%)
occurrences all number	164	101
Thrombocytopenia
subjects affected / exposed	45 / 348 (12.93%)	41 / 344 (11.92%)
occurrences all number	92	81
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	23 / 348 (6.61%)	12 / 344 (3.49%)
occurrences all number	26	12
Hypoacusis
subjects affected / exposed	29 / 348 (8.33%)	30 / 344 (8.72%)
occurrences all number	36	33
Tinnitus
subjects affected / exposed	59 / 348 (16.95%)	66 / 344 (19.19%)
occurrences all number	70	74
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	14 / 348 (4.02%)	18 / 344 (5.23%)
occurrences all number	16	24
Abdominal pain
subjects affected / exposed	11 / 348 (3.16%)	20 / 344 (5.81%)
occurrences all number	13	22
Constipation
subjects affected / exposed	178 / 348 (51.15%)	155 / 344 (45.06%)
occurrences all number	280	215
Diarrhoea
subjects affected / exposed	83 / 348 (23.85%)	66 / 344 (19.19%)
occurrences all number	112	92
Dry mouth
subjects affected / exposed	151 / 348 (43.39%)	158 / 344 (45.93%)
occurrences all number	217	215
Dyspepsia
subjects affected / exposed	23 / 348 (6.61%)	21 / 344 (6.10%)
occurrences all number	34	22
Nausea
subjects affected / exposed	210 / 348 (60.34%)	199 / 344 (57.85%)
occurrences all number	346	340
Dysphagia
subjects affected / exposed	143 / 348 (41.09%)	152 / 344 (44.19%)
occurrences all number	253	275
Odynophagia
subjects affected / exposed	62 / 348 (17.82%)	48 / 344 (13.95%)
occurrences all number	111	67
Oral pain
subjects affected / exposed	39 / 348 (11.21%)	43 / 344 (12.50%)
occurrences all number	69	78
Stomatitis
subjects affected / exposed	92 / 348 (26.44%)	96 / 344 (27.91%)
occurrences all number	167	184
Vomiting
subjects affected / exposed	112 / 348 (32.18%)	121 / 344 (35.17%)
occurrences all number	195	210
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	22 / 348 (6.32%)	20 / 344 (5.81%)
occurrences all number	23	20
Dermatitis
subjects affected / exposed	52 / 348 (14.94%)	42 / 344 (12.21%)
occurrences all number	88	67
Dry skin
subjects affected / exposed	18 / 348 (5.17%)	24 / 344 (6.98%)
occurrences all number	19	28
Erythema
subjects affected / exposed	24 / 348 (6.90%)	27 / 344 (7.85%)
occurrences all number	30	30
Pruritus
subjects affected / exposed	38 / 348 (10.92%)	24 / 344 (6.98%)
occurrences all number	51	38
Rash
subjects affected / exposed	43 / 348 (12.36%)	36 / 344 (10.47%)
occurrences all number	67	51
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	18 / 348 (5.17%)	22 / 344 (6.40%)
occurrences all number	42	37
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	24 / 348 (6.90%)	7 / 344 (2.03%)
occurrences all number	28	7
Hypothyroidism
subjects affected / exposed	51 / 348 (14.66%)	45 / 344 (13.08%)
occurrences all number	64	51
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	17 / 348 (4.89%)	20 / 344 (5.81%)
occurrences all number	18	25
Neck pain
subjects affected / exposed	30 / 348 (8.62%)	25 / 344 (7.27%)
occurrences all number	45	28
Infections and infestations
Oral candidiasis
subjects affected / exposed	25 / 348 (7.18%)	31 / 344 (9.01%)
occurrences all number	36	40
Pneumonia
subjects affected / exposed	36 / 348 (10.34%)	25 / 344 (7.27%)
occurrences all number	43	31
Upper respiratory tract infection
subjects affected / exposed	24 / 348 (6.90%)	21 / 344 (6.10%)
occurrences all number	28	23
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	128 / 348 (36.78%)	124 / 344 (36.05%)
occurrences all number	211	194
Dehydration
subjects affected / exposed	31 / 348 (8.91%)	29 / 344 (8.43%)
occurrences all number	38	33
Hyperglycaemia
subjects affected / exposed	31 / 348 (8.91%)	33 / 344 (9.59%)
occurrences all number	65	74
Hyperkalaemia
subjects affected / exposed	34 / 348 (9.77%)	32 / 344 (9.30%)
occurrences all number	49	66
Hypoalbuminaemia
subjects affected / exposed	42 / 348 (12.07%)	36 / 344 (10.47%)
occurrences all number	88	73
Hypocalcaemia
subjects affected / exposed	29 / 348 (8.33%)	23 / 344 (6.69%)
occurrences all number	42	37
Hypokalaemia
subjects affected / exposed	87 / 348 (25.00%)	71 / 344 (20.64%)
occurrences all number	179	130
Hypomagnesaemia
subjects affected / exposed	93 / 348 (26.72%)	84 / 344 (24.42%)
occurrences all number	178	173
Hyponatraemia
subjects affected / exposed	83 / 348 (23.85%)	68 / 344 (19.77%)
occurrences all number	183	164
Hypophosphataemia
subjects affected / exposed	23 / 348 (6.61%)	32 / 344 (9.30%)
occurrences all number	41	46

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

If a subject discontinued all 3 treatments of CRT phase due to death then death is included as discontinuation reason in each treatment disposition summary.Deaths reported as reason of discontinuation at any phase are included in all-cause mortality.

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