Supplemental Clinical Study Report
Protocol B9991016

CLINICAL STUDY REPORT SYNOPSIS
Investigational Product: Avelumab, Compound Number: MSB0010718C
Clinical Study Report Synopsis: Protocol B9991016
Protocol Title: 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
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Center(s): Refer to Appendix 16.1.4.1 for a list of sites involved in this study.
Publications Based on the Study: None.
Study Initiation Date: 28 November 2016
Study Completion Date: 25 August 2020
Report Date: 19 February 2021
Previous Report Date(s): Not applicable.
Phase of Development: Phase 3
Study Objectives and Endpoints: The primary objective for Study B9991016 was todemonstrate that treatment with avelumab in combination with standard of care (SOC)
chemoradiotherapy (CRT) is superior to SOC CRT alone in prolonging progression-freesurvival (PFS). The objectives and endpoints addressed in this supplemental clinical study
report (CSR) are summarized in Table S1.

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Table S1. Study Objectives and Endpoints Table
Type
SecondaryPharmacokinetics

Objective

Endpoint

 To evaluate the PK of Cmax and Ctrough for avelumab.
avelumab.
 AUCinf, Cmax, CL, Tmax, t½, Vz for To evaluate the PK of cisplatin
cisplatin (total and free), as data
(total and free).
permitted.
Immunogenicity
 To assess avelumab ADAs.
 ADA (nAb) against avelumab.
Biomarker
 To evaluate candidate immune  Tumor tissue biomarkers
related predictive biomarkers
including but not limited to,of sensitivity or insensitivity to
PD-L1 expression and tumor
treatment with avelumab +infiltrating CD8+ T-lymphocytes.
SOC CRT in tumor specimens(eg, PD-L1 expression) after 1
dose of avelumab in patients
who provide this optional
biopsy.
Safety To evaluate the overall safety
 AEs and laboratory abnormalities
and tolerability profile ofas graded by NCI-CTCAE v4.03.
avelumab in combination with
SOC CRT and placebo in
combination with SOC CRT.
Abbreviations: ADA = anti-drug antibodies; AE = adverse event; AUCinf = area under theconcentration-time curve extrapolated to infinity; CL = clearance; Cmax = maximum observed
concentration; CRT = chemoradiotherapy; Ctrough = predose concentration during multiple dosing;
PK = pharmacokinetics; NCI-CTCAE = National Cancer Institute common terminology criteria foradverse events; PD-L1 = programmed death-ligand 1; SOC = standard of care; t1/2 = elimination
half-life; Tmax = time to maximum plasma concentration; Vz = volume of distribution for
extravascular dosing.

METHODS
Study Design: Study B9991016 was a Phase 3, international, multicenter, randomized,
double-blind, parallel, 2-arm study in patients with previously untreated,histologically-confirmed locally advanced squamous cell carcinoma of the head and neck
(LA SCCHN, including oral cavity, oropharynx, larynx, or hypopharynx) who werecandidates for definitive CRT with cisplatin.
In this study, approximately 640 patients were to be randomized in a 1:1 ratio to either
Arm A (avelumab + SOC CRT) or Arm B (placebo + SOC CRT). Randomization was
stratified by tumor (T) stage (< T4 vs T4), nodal (N) stage (N0/N1/N2a/N2b vs N2c/N3), andhuman papilloma virus (HPV) status (positive vs negative) as measured by p16 expression byimmunohistochemistry (IHC).
There were 3 treatment phases in this study:
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CLINICAL STUDY REPORT SYNOPSIS

Lead-in Phase: On Day 1 of the Lead-in Phase of the study, patients received a single
dose of avelumab or matching placebo, administered 7 days prior to initiation of the
CRT Phase;

CRT Phase: Avelumab or matching placebo was administered on Days 8, 25, and 39
in conjunction with SOC CRT starting on Day 1 of the CRT phase;

Maintenance Phase: Following completion of the CRT Phase, avelumab or matchingplacebo was administered every 2 weeks (Q2W) for 12 months during theMaintenance Phase.

Diagnosis and Main Criteria for Inclusion: Patients aged 18 years or above, withpreviously diagnosed and untreated advanced SCCHN, Stage III, IVa, IVb HPV-negative
disease or Non-oropharyngeal HPV-positive disease, HPV-positive oropharyngeal disease
were candidates for definitive CRT with cisplatin.
Study Treatment: The study treatments included the following:
Arm A: Avelumab + SOC CRT:


Avelumab 10 mg/kg intravenous (IV): Day 1 of the Lead-in phase; Days 8, 25, and
39 of the CRT Phase; every 2 weeks (Q2W) for 12 months during the MaintenancePhase.

Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase.

Intensity-modulated radiation therapy (IMRT) 70 Gy/35 fractions/7 weeks;
1 fraction/day, 5 fractions/week for 7 weeks during the CRT Phase.

Arm B: Placebo + SOC CRT:

Placebo IV matching avelumab: Day 1 of the Lead-in phase; Days 8, 25, and 39 of
the CRT Phase; Q2W for 12 months during the Maintenance Phase.

Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase.



IMRT 70 Gy/35 fractions/7 weeks; 1 fraction/day, 5 fractions/week for 7 weeks during
the CRT Phase.

Note: The Day 25 dose of avelumab/placebo during the CRT Phase may be administered
between Day 24 and Day 29.
Efficacy Evaluations: Not applicable.
Pharmacokinetic, Immunogenicity, and Biomarker Evaluations:
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Pharmacokinetics: Blood samples of all patients were collected for pharmacokinetics (PK)analysis of avelumab. For the analysis of cisplatin blood samples were to be collected in a
total of 24 patients (12 patients in avelumab + SOC CRT arm and 12 patients in placebo +SOC CRT arm) at selected sites. PK parameters analyzed included minimum plasma
concentration (Ctrough), maximum plasma concentration (Cmax) for avelumab and area under
the concentration-time curve extrapolated to infinity (AUCinf), Cmax, clearance (CL), time tomaximum plasma concentration (Tmax), elimination half-life (t1/2), and volume of distribution(Vz) for cisplatin (total and free), as data permitted.
Immunogenicity: Blood samples were collected and assessed for development of avelumab
anti-drug antibodies (ADAs). Samples that were positive for ADA were to undergo
neutralizing antibody (nAb) characterization.
Biomarker: Tumor biospecimens representing tissue samples from tumor resection or
biopsy were used to analyze programmed death-ligand 1 (PD-L1) expression and tumor
infiltrating CD8+ T-lymphocytes by IHC. Samples obtained during the Lead-in Phase(optional), Maintenance Phase (in patients who undergo a clinically indicated tumor
resection), and/or at the End of Treatment/Withdrawal visit (all patients) were assessed inparallel with the mandatory pretreatment biospecimens(s) to provide data on the changes inthe tumor that accumulated over the course of therapy, including acquired mechanisms ofresistance.
Safety Evaluations: Safety assessments included collection of adverse events (AEs),
Serious Adverse Events (SAEs), vital signs, physical examination, electrocardiogram (ECG,
12-lead), and laboratory assessments (including pregnancy tests).
Statistical Methods:
Pharmacokinetics: Ctrough and Cmax for avelumab were to be summarized descriptively (n,mean, SD, CV, median, minimum, maximum, geometric mean, its associated CV, and 95%
CI) by treatment phase, and day in Arm A. PK parameters for cisplatin (total and free) were
to be estimated using noncompartmental and/or compartment methods. Analyses also
included Cmax, time to Tmax, AUCinf, t½, CL, and Vz as data permitted.
Additionally, avelumab PK were to be evaluated following cisplatin dosing by comparing theoverall geometric mean ratios of Cmax and Ctrough in only Arm A on Day 8 of the CRT Phase
to Day 1 of the Lead-in Phase. Cisplatin PK (total and free) were evaluated following
avelumab or placebo dosing by comparing the overall geometric mean ratios of Cmax and
AUCinf on Day 1 of the CRT Phase in Arm A to Day 1 of the CRT Phase in Arm B.
Immunogenicity: The immunogenicity data were summarized as the percentage of patientswith positive ADA and nAb.
Biomarker: Summary statistics for on-treatment biomarkers included the ratio to baseline
for continuous biomarkers.
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Safety: All analyses were based on treatment-emergent adverse events (TEAEs) (started
during the on-treatment period), if not otherwise specified. The AE listings included all AEs(whether treatment-emergent or not). AEs with onset outside the on-treatment period were
flagged in the listings.
The frequency (number and percentage) of patients with SAEs by system organ class andpreferred term (PT) and related SAEs by system organ class and PT were presented fortreatment-emergent SAEs by treatment arm. Listings of all SAEs were also provided withthe relevant information with a flag for SAEs with onset outside of the on-treatment period.
Laboratory results were classified according to the National Cancer Institute common
terminology criteria for AEs (NCI-CTCAE) criteria version 4.03. Quantitative data oflaboratory values and vital signs were summarized using simple descriptive statistics (mean,SD, median, Q1, Q3, minimum, and maximum) of actual values and changes from baseline
for each nominal visit over time. End of Treatment visit laboratory results were summarized
separately.
RESULTS
Subject Disposition and Demography: Table S2 presents a summary of patient disposition
by study phase. A total of 697 patients were randomized. A smaller number of patients inthe avelumab + SOC CRT group versus placebo + SOC CRT group completed themaintenance phase.
No patient discontinuations were reported as due to coronavirus disease 19 (COVID-19)
related study disruptions.
Overall, demographic characteristics were balanced across treatment arms. Most enrolled
patients were males, most were  65 years old, and the majority were White. Refer to theB9991016 final study report dated 25 Jun 2020 for additional details on demographic andbaseline characteristics.
Table S2. Subject Disposition by Study Phase - Full Analysis Set (Protocol B9991016)
Avelumab + SOC CRT(N = 350)

Placebo + SOC CRT(N = 347)

n (%)

n (%)

5 (1.4)4 (1.2)0

1 (0.3)

Disposition : Lead-In phase
Discontinued
Reason for discontinuation
Death
Adverse event
No longer meets eligibility criteria

3 (0.9)00

1 (0.3)

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Table S2. Subject Disposition by Study Phase - Full Analysis Set (Protocol B9991016)
Avelumab + SOC CRT(N = 350)

Placebo + SOC CRT(N = 347)

n (%)

n (%)

2 (0.6)2 (0.6)

Completed

345 (98.6)

343 (98.8)

Ongoing00Subjects entering CRT phase345 (98.6)

340 (98.0)

Discontinued

33 (9.4)

27 (7.8)

Withdrawal by subject

Disposition : CRT phase for Avelumab or Placebo

Reason for discontinuationDeath

5 (1.4)8 (2.3)Adverse event

12 (3.4)

12 (3.5)

Physician decision

2 (0.6)

1 (0.3)Global deterioration of health status

1 (0.3)0

Withdrawal by subject

10 (2.9)4 (1.2)

Lost to follow-up

1 (0.3)1 (0.3)2 (0.6)

1 (0.3)CompletedOther

312 (89.1)

313 (90.2)

Ongoing00Subjects entering CRT phase345 (98.6)

340 (98.0)

Discontinued

111 (31.7)

104 (30.0)

Death

3 (0.9)8 (2.3)Adverse event

82 (23.4)

81 (23.3)

Physician decision

12 (3.4)

10 (2.9)

Disposition : CRT phase for Cisplatin

Reason for discontinuation

Global deterioration of health status

1 (0.3)0

Withdrawal by subject

11 (3.1)

3 (0.9)Lost to follow-up

1 (0.3)1 (0.3)Other

1 (0.3)1 (0.3)Completed

234 (66.9)

236 (68.0)

Ongoing00Subjects entering CRT phase345 (98.6)

340 (98.0)

Discontinued

23 (6.6)

20 (5.8)Death

5 (1.4)8 (2.3)Adverse event

5 (1.4)5 (1.4)Global deterioration of health status

1 (0.3)0

Disposition : CRT phase for IMRT

Reason for discontinuation

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Table S2. Subject Disposition by Study Phase - Full Analysis Set (Protocol B9991016)
Avelumab + SOC CRT(N = 350)

Placebo + SOC CRT(N = 347)

n (%)

n (%)

Withdrawal by subject

10 (2.9)

6 (1.7)

Lost to follow-up

1 (0.3)1 (0.3)Other

1 (0.3)0Completed

322 (92.0)

320 (92.2)

Ongoing00Subjects entering Maintenance phase291 (83.1)

304 (87.6)

Discontinued

152 (43.4)

127 (36.6)

Disposition : Maintenance phase

Reason for discontinuationDeath

17 (4.9)

11 (3.2)

Progressive disease60 (17.1)

54 (15.6)

Adverse event

24 (6.9)

21 (6.1)

Non-compliance with study drug

1 (0.3)1 (0.3)

Physician decision

1 (0.3)1 (0.3)Global deterioration of health status

14 (4.0)5 (1.4)

Withdrawal by subject

31 (8.9)25 (7.2)

Lost to follow-up

1 (0.3)2 (0.6)

Study terminated by sponsor

1 (0.3)6 (1.7)Other

2 (0.6)

1 (0.3)Completed

139 (39.7)

177 (51.0)

Ongoing00Subjects entering Follow-Up

266 (76.0)

284 (81.8)

Discontinued

58 (16.6)

68 (19.6)

Death

12 (3.4)

10 (2.9)

Withdrawal by subject

6 (1.7)2 (0.6)

Disposition : Follow-Up phase

Reason for discontinuation

Lost to follow-up

1 (0.3)1 (0.3)

Study terminated by sponsor

32 (9.1)

50 (14.4)

7 (2.0)5 (1.4)CompletedOther

208 (59.4)

216 (62.2)

Ongoing00Subjects entering Long-Term Follow-Up

247 (70.6)

237 (68.3)

Discontinued

247 (70.6)

237 (68.3)

Disposition : Long-Term Follow-Up phase

Reason for discontinuation

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Table S2. Subject Disposition by Study Phase - Full Analysis Set (Protocol B9991016)
Avelumab + SOC CRT(N = 350)

Placebo + SOC CRT(N = 347)

n (%)

n (%)

Death

51 (14.6)

31 (8.9)

Withdrawal by subject

7 (2.0)1 (0.3)

Lost to follow-up

2 (0.6)4 (1.2)187 (53.4)

201 (57.9)

00Study terminated by sponsor
Ongoing

The denominator to calculate percentages is N, the number of subjects in the full analysis set within each treatment group.
PFIZER CONFIDENTIAL SDTM Creation: 02OCT2020 (14:21) Source Data: ADDS Output
File: ./B9991016/B9991016_sCSR/adds_s001a1 Date of Generation: 07OCT2020 (01:17) Snapshot Date: 02OCT2020
Table 14.1.1.2.2.1 is for Pfizer internal use.

Efficacy Results: Refer to the B9991016 final study report dated 25 June 2020 for
presentation of efficacy results.
Pharmacokinetic Results:
Avelumab: Serum avelumab Cmax and Ctrough concentrations are presented by study phaseand visit in Figure S1. Mean serum avelumab concentrations were similar at 1 hour post
infusion for each study phase and visit and Ctrough increased over time even after reachingstate steady.

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Figure S1 Box-Plots of Serum Trough and Maximum Concentration for Avelumab by
Study Phase and Visit - Avelumab PK Concentration Analysis Set

Source: Figure 14.4.4.1.

The effect of cisplatin treatment on the avelumab PK parameter Cmax on Day 8 of the CRT
Phase compared to Day 1 of the Lead-in Phase is presented in Figure S2. The observed mean
avelumab Cmax values were similar at Day 1 and Day 8 of treatment, indicating no effect.

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Figure S2 Box-Plots of Avelumab Cmax in the Absence (Lead-in Day 1) and Presenceof Cisplatin (CRT Day 8) - Avelumab PK Parameter Analysis Set Treatment Group = Avelumab + SOC CRT

Source: Figure 14.4.5.2.

Cisplatin: Cisplatin PK samples were collected from 12 patients in the avelumab + SOC
CRT group and 23 patients in the placebo + SOC CRT group. Median total plasma cisplatinconcentration and cisplatin PK parameters are presented in Figure S3 and Table S3,
respectively. AUClast is reported instead of AUCinf because AUCinf could not be calculated.
The observed GM ratio of AUClast for total cisplatin was numerically lower in the
avelumab + SOC CRT group compared to the placebo + SOC CRT group, but is notconsidered meaningful as the 90% confidence intervals (CIs) overlap with 100 (geometricmean [GM] ratio = 89.90, 90% CI = 78.06, 103.55; Table S4).

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Table S3. Summary of Total Cisplatin Pharmacokinetics Parameters by Treatment
Group on Day 1 of the CRT Phase - Cisplatin PK Parameter Analysis Set(Protocol B9991016)
Nn

Avelumab + SOC CRTNnPlacebo + SOC CRT

AUClast (ng.hr/mL)

121044500(43)232051040(35)

AUClast, dn (ng.hr/mL/mg)

1210299.1(30)2320

332.7(17)Cmax (ng/mL)

12

123781(44)23

234001(34)

Cmax, dn (ng/mL/mg)

121226.23(36)23

23

25.33(26)

Tlast (hr)1210

22.10(19.9, 26.5)

2320

23.95(20.8, 28.1)

Tmax (hr)12121.000(0.500, 2.40)

23

23

1.170(0.983, 24.0)

Geometric mean (geometric %CV) for all except: median (range) for Tlast and Tmax.
N = Number of subjects in the treatment group.
n = Number of subjects contributing to the statistical summary.
PK parameters with zero values were excluded from the calculation of geometric means and its associated %CV.
PFIZER CONFIDENTIAL SDTM Creation: 05NOV2020 (21:04) Source Data: ADPP Output
File: ./B9991016/B9991016_PK/adpp_s002 Date of Generation: 05NOV2020 (23:11) Cutoff Date: 13MAR2020 Snapshot
Date: 02OCT2020
Table 14.4.5.3 is for Pfizer internal use.

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Table S4. Effect of Study Treatment on Total Cisplatin Pharmacokinetics Parameters(Cmax, dn, AUClast, dn) on Day 1 of the CRT Phase - Cisplatin PK Parameter
Analysis Set (Protocol B9991016)
AUClast, dn, ng.hr/mL/mg
Avelumab + SOC CRT

Placebo + SOC CRT

Avelumab + SOC CRT vs Placebo + SOC
CRT

Cmax, dn, ng/mL/mg

n

10

12

GM

299.1

26.23

GM CV (%)

30

36

GM 95% CI(242.7, 368.5)(21.05, 32.67)

n

20

23

GM

332.7

25.33

GM CV (%)

17

26

GM 95% CI(307.9, 359.4)(22.71, 28.25)

n

30

35

GM Ratio

89.90

103.53

GM 90% CI(78.06, 103.55)(87.09, 123.07)

PK parameters with zero values were excluded from the calculation of geometric means and its associated %CV.
GM = Geometric mean.
PFIZER CONFIDENTIAL SDTM Creation: 05NOV2020 (21:04) Source Data: ADPP Output
File: ./B9991016/B9991016_PK/adpp_s003 Date of Generation: 06NOV2020 (03:35) Cutoff Date: 13MAR2020 Snapshot
Date: 02OCT2020
Table 14.4.5.5 is for Pfizer internal use.

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Figure S3 Median Plasma Total Cisplatin Concentrations by Treatment Group in the
CRT Phase (Log Scale) - Cisplatin PK Concentration Analysis Set

Source: Figure 14.4.4.4.

Immunogenicity Results:
Subject ADA categories are summarized in Table S5. Treatment-induced ADA responses
occurred in 47 (15.3%) patients who received avelumab in combination with SOC CRT. No
patients who were baseline ADA positive had treatment-boosted ADA.
Tests for nAbs were not performed.

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Table S5. Summary of Subject ADA Categories - Immunogenicity Analysis Set(Protocol B9991016)
Avelumab + SOC CRT(N = 331)n (%)

Subjects with at least one valid ADA result at any time point (N0)331 (100.0)

Subjects with valid baseline ADA result (N1)324 (97.9)

Subjects with valid baseline ADA results and at least one valid post-baseline ADA result (N2)313 (94.6)

Subjects with at least one valid post-baseline ADA result and without positive baseline ADA
result (N3)307 (92.7)

ADA never-positive (n/N0)277 (83.7)

ADA ever-positive (n/N0)54 (16.3)

Baseline ADA positive (n/N1)

7 (2.2)Treatment-boosted ADA (n/N2)0Treatment-induced ADA (n/N3)

47 (15.3)

Transient ADA response (n/N3)

22 (7.2)

Persistent ADA response (n/N3)

25 (8.1)

Baseline is defined as the last assessment on or prior to the date/time of the first dose of avelumab.
The denominator to calculate percentages for N0, N1, N2, N3 is N, the number of subjects in the immunogenicity analysis
set.
PFIZER CONFIDENTIAL SDTM Creation: 05NOV2020 (00:25) Source Data: ADIS Output
File: ./B9991016/B9991016_ADA/adis_s001 Date of Generation: 05NOV2020 (02:08) Cutoff Date: 13MAR2020 Snapshot
Date: 02OCT2020
Table 14.4.9.1.1 is for Pfizer internal use.

Biomarker Results:
Pre-treatment PD-L1 expression based on immune cells and tumor cells and tumor
infiltrating CD8+ T-lymphocytes as assessed by IHC were candidate predictive biomarkers
in this study. The numbers of patients included in the analysis with both pre- andpost-treatment biomarker data available were 36 patients for PD-L1 positive immune cells
and PD-L1 tumor staining (13 patients and 23 patients from the avelumab + SOC CRT andplacebo + SOC CRT arms, respectively), and 35 patients for CD8+ cells (13 patients and22 patients from the avelumab + SOC CRT and placebo + SOC CRT arms, respectively).
The median change in the number of PD-L1-positive immune cells from pre- topost-treatment was 0.0 and -3.0 for the avelumab + SOC CRT arm and placebo + SOC CRT
arm, respectively. The median change in PD-L1-positive tumor cells from pre- topost-treatment was 0.0 for both the avelumab + SOC CRT arm and placebo + SOC CRT arm.
The median change in CD8+ cells total area from pre- to post-treatment was 0.2 and 0.6 forthe avelumab + SOC CRT arm and placebo + SOC CRT arm, respectively. No significant
differences were detected between the treatment arms (p = 0.141, p = 0.614, and p = 0.839
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for change from baseline in PD-L1 positive immune cells, PD-L1 tumor staining, and CD8+
cells total area, respectively).
Additional biomarker data will be presented in a future report.
Safety Results:
Overall, the proportion of patients who reported AEs was similar across treatment arms
except for a higher incidence (defined as ≥ 5% difference) of all-causality andtreatment-related TEAEs of Grade ≥ 3 and TEAEs leading to dose interruption of avelumab
or placebo in the avelumab + SOC CRT arm in comparison to the placebo + SOC CRT arm.
Relevant differences in the frequency of TEAEs were observed for the PTs of Constipation,
Pyrexia, Leukopenia, Neutrophil count decreased, Odynophagia, Alanine aminotransferase
increased, Aspartate aminotransferase increased, Chills, and Pharyngeal inflammation(Table S6). Relevant differences in the frequency of treatment-related TEAEs were observed
for the PTs of Weight decreased, Leukopenia, Neutrophil count decreased, Odynophagia,
Pyrexia, Alanine aminotransferase increased, Aspartate aminotransferase increased, Chills,
and Pharyngeal inflammation.
TEAEs leading to discontinuation of avelumab, cisplatin, or IMRT occurred at similarfrequencies in both treatment arms. The most common TEAE leading to discontinuation of
avelumab was Infusion-related reaction (IRR) and for cisplatin was Neutropenia and Bloodcreatinine increased. TEAEs leading to discontinuation of IMRT were all single occurrences.
Deaths occurred more frequently in the avelumab + SOC CRT arm and were most often due
to disease progression. The most frequent TEAEs leading to death were those in the systemorgan class of Infections and infestations (5 patients [1.4%] in the avelumab + SOC CRT arm
and no patients in the placebo + SOC CRT treatment arm).
A summary of serious TEAEs occurring in ≥2% subjects in any treatment group is presented
in Table S7.
Refer to the B9991016 final study report dated 25 June 2020 for the presentation of immunerelated AEs (irAEs) and IRRs in this study.

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Table S6. Summary of Most Common TEAEs (Any Grade in ≥ 10% Subjects orGrade ≥ 3 in ≥ 2% Subjects in Any Treatment Group), by PT and
Maximum CTCAE Grade During the On-Treatment Period - Safety
Analysis Set (Protocol B9991016)
Avelumab + SOC CRT(N = 348)

Placebo + SOC CRT(N = 344)

Preferred Term
All Grades(n %)Grade ≥ 3(n %)All Grades(n %)Grade ≥ 3(n %)Subjects with events

345 (99.1)

305 (87.6)

342 (99.4)

281 (81.7)

Nausea210 (60.3)

23 (6.6)

201 (58.4)

17 (4.9)

Anaemia

206 (59.2)

52 (14.9)

193 (56.1)

56 (16.3)

Constipation

178 (51.1)

7 (2.0)155 (45.1)

3 (0.9)Weight decreased

160 (46.0)

28 (8.0)172 (50.0)

28 (8.1)

Dry mouth

151 (43.4)

5 (1.4)158 (45.9)

4 (1.2)Dysphagia

146 (42.0)

58 (16.7)

155 (45.1)

54 (15.7)

Mucosal inflammation

146 (42.0)

50 (14.4)

131 (38.1)

47 (13.7)

Radiation skin injury

135 (38.8)

19 (5.5)

136 (39.5)

17 (4.9)

Decreased appetite

129 (37.1)

25 (7.2)

124 (36.0)

20 (5.8)

Fatigue

116 (33.3)

15 (4.3)

128 (37.2)

13 (3.8)

Vomiting

114 (32.8)

19 (5.5)

125 (36.3)

24 (7.0)

Dysgeusia

106 (30.5)

0119 (34.6)

2 (0.6)

Neutropenia

106 (30.5)

58 (16.7)

100 (29.1)

53 (15.4)

Pyrexia

96 (27.6)

4 (1.1)47 (13.7)

3 (0.9)Stomatitis

96 (27.6)

25 (7.2)

97 (28.2)

26 (7.6)

Hypomagnesaemia

93 (26.7)

4 (1.1)84 (24.4)

4 (1.2)

Hypokalaemia

89 (25.6)

34 (9.8)

73 (21.2)

30 (8.7)

Blood creatinine increased

88 (25.3)

7 (2.0)73 (21.2)

5 (1.5)

Hyponatraemia

84 (24.1)

40 (11.5)

70 (20.3)

38 (11.0)

Diarrhoea

83 (23.9)9 (2.6)67 (19.5)

8 (2.3)

Oropharyngeal pain

75 (21.6)

14 (4.0)

92 (26.7)

8 (2.3)

Cough

74 (21.3)

2 (0.6)64 (18.6)

0White blood cell count decreased

69 (19.8)

34 (9.8)64 (18.6)

28 (8.1)

Asthenia

65 (18.7)

15 (4.3)

62 (18.0)

11 (3.2)

Leukopenia

64 (18.4)

22 (6.3)

46 (13.4)

20 (5.8)

Neutrophil count decreased

64 (18.4)

41 (11.8)

60 (17.4)

31 (9.0)

Odynophagia

64 (18.4)

16 (4.6)

48 (14.0)

3 (0.9)Tinnitus

59 (17.0)0

67 (19.5)0Alanine aminotransferase increased

57 (16.4)

8 (2.3)30 (8.7)

1 (0.3)

Insomnia

57 (16.4)

1 (0.3)47 (13.7)

0

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Supplemental Clinical Study Report
Protocol B9991016

CLINICAL STUDY REPORT SYNOPSIS
Table S6. Summary of Most Common TEAEs (Any Grade in ≥ 10% Subjects orGrade ≥ 3 in ≥ 2% Subjects in Any Treatment Group), by PT and
Maximum CTCAE Grade During the On-Treatment Period - Safety
Analysis Set (Protocol B9991016)
Avelumab + SOC CRT(N = 348)

Placebo + SOC CRT(N = 344)

Preferred Term
All Grades(n %)Grade ≥ 3(n %)All Grades(n %)Grade ≥ 3(n %)Aspartate aminotransferase increased

55 (15.8)

3 (0.9)26 (7.6)

3 (0.9)Pneumonia

54 (15.5)

23 (6.6)

38 (11.0)

24 (7.0)

Dermatitis

52 (14.9)

4 (1.1)42 (12.2)

4 (1.2)Dysphonia

51 (14.7)

047 (13.7)

1 (0.3)

Hypothyroidism51 (14.7)

045 (13.1)

0Thrombocytopenia

46 (13.2)

4 (1.1)41 (11.9)

5 (1.5)

Headache45 (12.9)

2 (0.6)41 (11.9)

2 (0.6)Rash

43 (12.4)

3 (0.9)36 (10.5)

0Hypoalbuminaemia

42 (12.1)

3 (0.9)37 (10.8)

3 (0.9)Dizziness

41 (11.8)

1 (0.3)33 (9.6)0Chills40 (11.5)

1 (0.3)7 (2.0)0

Lymphocyte count decreased

40 (11.5)

31 (8.9)42 (12.2)

32 (9.3)

Oral pain

40 (11.5)

10 (2.9)44 (12.8)

12 (3.5)

Platelet count decreased

40 (11.5)

6 (1.7)33 (9.6)

2 (0.6)

Productive cough40 (11.5)

1 (0.3)32 (9.3)

1 (0.3)Dehydration

39 (11.2)

11 (3.2)

42 (12.2)

16 (4.7)

Pruritus

38 (10.9)

024 (7.0)0

Dyspnoea

35 (10.1)

7 (2.0)39 (11.3)

9 (2.6)Hyperkalaemia

34 (9.8)

4 (1.1)32 (9.3)

8 (2.3)Lymphopenia

33 (9.5)

21 (6.0)27 (7.8)

16 (4.7)

Hyperglycaemia

32 (9.2)

8 (2.3)33 (9.6)6 (1.7)Hypertension

32 (9.2)

12 (3.4)

28 (8.1)

15 (4.4)

Acute kidney injury

27 (7.8)

10 (2.9)30 (8.7)

8 (2.3)

Pharyngeal inflammation

24 (6.9)9 (2.6)23 (6.7)

2 (0.6)

Hypophosphataemia

23 (6.6)

9 (2.6)32 (9.3)

9 (2.6)Amylase increased

22 (6.3)

7 (2.0)10 (2.9)4 (1.2)

Lipase increased

14 (4.0)

7 (2.0)9 (2.6)

1 (0.3)

Laryngeal oedema

13 (3.7)

7 (2.0)11 (3.2)

5 (1.5)Febrile neutropenia

11 (3.2)

7 (2.0)9 (2.6)9 (2.6)

Pneumonia aspiration

10 (2.9)5 (1.4)13 (3.8)

7 (2.0)PFIZER CONFIDENTIAL
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Supplemental Clinical Study Report
Protocol B9991016

CLINICAL STUDY REPORT SYNOPSIS
Table S6. Summary of Most Common TEAEs (Any Grade in ≥ 10% Subjects orGrade ≥ 3 in ≥ 2% Subjects in Any Treatment Group), by PT and
Maximum CTCAE Grade During the On-Treatment Period - Safety
Analysis Set (Protocol B9991016)
Avelumab + SOC CRT(N = 348)

Placebo + SOC CRT(N = 344)

Preferred Term
All Grades(n %)Grade ≥ 3(n %)All Grades(n %)Grade ≥ 3(n %)The denominator to calculate percentages is N, the number of subjects in the safety analysis set within each treatment group.
Subjects reporting more than one adverse event (AE) within a preferred term are counted only once in that preferred term.
For subjects reporting more than one AE within a preferred term, the AE with maximum grade is included in the table.
MedDRA v23.0 coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 02OCT2020 (12:54) Source Data: ADAE Output
File: ./B9991016/B9991016_sCSR/adae_s999a Date of Generation: 07OCT2020 (01:20) Snapshot Date: 02OCT2020
Table 14.3.1.3.1.17 is for Pfizer internal use.

PFIZER CONFIDENTIAL
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Supplemental Clinical Study Report
Protocol B9991016

CLINICAL STUDY REPORT SYNOPSIS
Table S7. Summary of Most Common Serious TEAEs ≥ 2% Subjects in Any
Treatment Group by PT During the On-Treatment Period - Safety Analysis
Set (Protocol B9991016)
Avelumab + SOC CRT(N = 348)

Placebo + SOC CRT(N = 344)

All Grades(n %)All Grades(n %)Subjects with events

184 (52.9)

177 (51.5)

Pneumonia

25 (7.2)

20 (5.8)

Dysphagia

15 (4.3)

13 (3.8)

Acute kidney injury

12 (3.4)

11 (3.2)

Pyrexia

12 (3.4)

3 (0.9)Vomiting

11 (3.2)

13 (3.8)

Dehydration

9 (2.6)15 (4.4)

Febrile neutropenia

9 (2.6)5 (1.5)

Anaemia

8 (2.3)

12 (3.5)

Blood creatinine increased

7 (2.0)6 (1.7)

Nausea7 (2.0)9 (2.6)

Sepsis7 (2.0)5 (1.5)

Stomatitis

7 (2.0)4 (1.2)

Dyspnoea

5 (1.4)7 (2.0)

Hyponatraemia

4 (1.1)7 (2.0)Preferred Term

The denominator to calculate percentages is N, the number of subjects in the safety analysis set within each treatment group.
Subjects reporting more than one adverse event (AE) within a preferred term are counted only once in that preferred term.
For subjects reporting more than one AE within a preferred term, the AE with maximum grade is included in the table.
MedDRA v23.0 coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 02OCT2020 (12:54) Source Data: ADAE Output
File: ./B9991016/B9991016_sCSR/adae_s999c Date of Generation: 07OCT2020 (01:19) Snapshot Date: 02OCT2020
Table 14.3.1.3.1.19 is for Pfizer internal use.

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Supplemental Clinical Study Report
Protocol B9991016

CLINICAL STUDY REPORT SYNOPSIS
Conclusions:

In general, PK results for avelumab were consistent with previously observed
exposures in patients with SCCHN with no indication of drug interaction between
avelumab and cisplatin.

The observed incidence of ADA in patients treated with avelumab was consistent
with the incidence of ADA in previous studies of avelumab.

No significant differences were noted between treatment groups in change frombaseline of PD-L1 expression or the presence of CD8+ cells following 1 dose oftherapy.

The safety profile of avelumab administered in combination with CRT was generally
tolerable, manageable, and consistent with the known safety profiles of avelumab andchemotherapy when administered as monotherapies. No new important signals werenoted in the updated safety data compared to data reported in the Final CSR.

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