Final Clinical Study Report
Protocol B9991024

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc.
Investigational Product: Avelumab, Axitinib
Clinical Study Report Synopsis: Protocol B9991024
Protocol Title: An Open Label, Single Arm Phase 1B Study of Avelumab Plus Axitinib asFirst Line Treatment in Patients With Advanced Hepatocellular Carcinoma
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Center(s): Seven centers in Japan participated in the study. Refer toAppendix 16.1.4.1 for a list of sites involved in this study.
Publications Based on the Study: None
Study Initiation Date: 08 September 2017
Study Completion Date: 25 October 2019
Report Date: 13 July 2020
Previous Report Date(s): Not applicable
Phase of Development: Phase 1b
Primary and Secondary Study Objectives and Endpoints: The study objectives andendpoints of this study are presented in Table S1.

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Table S1.

Study Objectives and Endpoints

Type
Primary
SafetyObjective

Endpoint

To evaluate the safety and tolerabilityof avelumab in combination withaxitinib as first line treatment inpatients with advanced HCC.

AEs and laboratory abnormalities asgraded by NCI CTCAE v4.03.

Secondary
Efficacy

To evaluate antitumor effect of
TTP, PFS, OR, DC, TTR and DR, peravelumab in combination with axitinib RECIST v1.1.
as first line treatment in patients withadvanced HCC per RECIST v1.1.
To evaluate the OS of avelumab inOS.
combination with axitinib in patientswith advanced HCC.
PK
To evaluate the PK of avelumab andPK parameters including trough andaxitinib when administered in
maximum concentrations (Ctrough, Cmax)
combination.
of avelumab and axitinib.
Pharmacodynamics
To evaluate candidate predictive
Tumor tissue biomarker status (ie,biomarkers in pre-treatment tumor
positive or negative based on, eg,
tissue that could aid in the
PD-L1 expression and/or quantitation ofidentification of a patient
tumor-infiltrating CD8+ T lymphocytes
subpopulation most likely to benefit
as assessed by IHC).
from treatment with avelumab in
combination with axitinib.
Immunogenicity
To assess the immunogenicity of
ADAs and nAbs for avelumab when in
avelumab when combined withcombination with axitinib.
axitinib.
Abbreviations: ADA=anti-drug antibodies; AE=adverse event; Cmax=maximum observed concentration;
CTCAE=Common Terminology Criteria for Adverse Events; Ctrough=predose concentration during multiple
dosing; DC=disease control; DR=duration of response; HCC=hepatocellular carcinoma;
IHC=immunohistochemistry; nAb=neutralizing antibody; NCI=National Cancer Institute; OR=objective
response; OS=overall survival; PD-L1=programmed death Ligand 1; PFS=progression-free survival;
PK=pharmacokinetic; RECIST=Response Evaluation Criteria in Solid Tumors; TTP=time to progression;
TTR=time to tumor response.

METHODS
Study Design: This was an open-label, multicenter, single arm, Phase 1b study to evaluate
the safety, efficacy and pharmacokinetic (PK) of avelumab in combination with axitinib asfirst line treatment in patients with advanced hepatocellular carcinoma (HCC).
Twenty-two patients with advanced HCC who did not have the prior systemic therapy wereenrolled in this study. The overall safety profile of these patients was assessed after aminimum follow-up of 3 months (ie, at least 3 months from the last patient first dosing).
Significant toxicities including immune-related adverse events (irAEs) which occurred up to
3 months of follow-up after the last dose of study treatment were also to be included in theassessment. Patients received avelumab 10 mg/kg every 2 weeks (Q2W) in combination
with axitinib 5 mg twice daily (BID). If this dose level for the combination was not
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tolerable, a lower axitinib dose in the combination (avelumab 10 mg/kg [intravenous {IV}]Q2W plus axitinib 3 mg BID) may have been evaluated with adding new cohorts of patients.
In addition, a cohort of patients aimed to evaluate avelumab 800 mg flat dose Q2W in
combination with axitinib 5 mg BID may have been added after the tolerability of avelumab
10 mg/kg Q2W in combination with axitinib 5 mg BID was confirmed.
Diagnosis and Main Criteria for Inclusion:
Diagnosis of locally advanced or metastatic HCC, obtained by histology/cytology (on a priortumor biopsy) or by imaging (acceptable imaging modalities include triphasic
contrast-enhanced helical computerized tomography [CT], triphasic dynamic
contrast-enhanced magnetic resonance imaging [MRI] and contrast-enhanced
ultrasonography) with serum -fetoprotein ≥400 ng/mL, and the patients who had provided
at least 1 archival tumor specimen. If archival tumor specimen was no longer available,
de novo tumor biopsy was required during screening were included in the study.
Patients with prior systemic treatment for advanced HCC, including prior treatment withapproved or investigational drugs and with any prior locoregional therapy (such as hepatic
arterial embolization, targeted through the hepatic artery combined with embolization,
hepatic arterial infusion, radiofrequency ablation, percutaneous ethanol injection or
cryoablation) within 4 weeks and radiotherapy or surgical procedure within 2 weeks(4 weeks for major surgery) of starting the study treatment were excluded from the study.
Prior palliative radiotherapy to metastatic lesion(s) was permitted, provided it had been
completed at least 48 hours prior to starting the study treatment.
Study Treatment:
Avelumab was formulated as a 20.0 mg/mL solution and was supplied by the sponsor insingle-use glass vials, stoppered with a rubber septum and sealed with an aluminum
polypropylene flip-off seal. For application in this study, avelumab drug product was diluted
with 0.9% saline solution (sodium chloride injection). Avelumab was administered on Day 1
of each 14-day cycle after all procedures/assessments had been completed, and it may havebeen administered up to 3 days before or after the scheduled Day 1 of each dose.
Avelumab was administered as a 1-hour IV infusion Q2W. In order to mitigate avelumab
infusion‑related reactions, patients had to be premedicated approximately 30 to 60 minutes
prior to the first 4 infusions of avelumab. Premedication should have been administered for
subsequent avelumab doses based upon clinical judgment and presence/severity of priorinfusion reactions. Premedication included an antihistamine (eg, 25-50 mg diphenhydramine
IV or oral equivalent), and paracetamol (acetaminophen) (eg, 500-650 mg paracetamol[acetaminophen] IV or oral equivalent).
Axitinib was administered orally BID at approximately the same time in the morning andevening on a continuous dosing schedule, ie, without a break in dosing in the absence ofdrug-related toxicity. Axitinib tablets were to be taken approximately 12 hours apart and
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could have been administered without regard to meals. Tablets were not to be crushed, split,
or dissolved, and patients were instructed to swallow the study medication whole without
manipulation or chewing of the medication prior to swallowing. The study drug information
is provided in Table S2.
Table S2. Study Drug Description
Study Drug Description
AG-013736 1 mg A immediate releasefilm coated tablet
AG-013736 5 mg immediate releasefilm coated tablet
MSB0010718C solution for infusion,
20 mg/mL (10 mL/vial)

Vendor Lot
Number
L34589Pfizer Lot
Number15-004995

Strength/Potency

Dosage Form

1 mg

TabletL2242215-004998

5 mg

Tablet

PD1G001

16-000917

200 mgSolution

Efficacy Evaluations:
In this study, the efficacy evaluation included assessment of antitumor activity. Tumor
assessments included all known or suspected disease sites. Imaging may have included
chest, abdomen, and pelvis CT or MRI scans; it could also include brain CT or MRI scan atbaseline and whenever brain metastases were suspected. The CT and MRI scans were
performed with contrast agents unless contraindicated for medical reasons. The same
imaging technique used to characterize each identified and reported lesion at baseline was
employed for tumor assessments. The antitumor activity was assessed based on Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1 through radiological tumor assessments
for secondary endpoints.
The efficacy evaluations were conducted at baseline, and every 8 weeks thereafter until
confirmed progressive disease (PD) per RECIST v1.1 and at the end oftreatment (EOT)/withdrawal.
Pharmacokinetic, Pharmacodynamic and Immunogenicity Evaluations:Pharmacokinetics
The PK evaluation in this study included calculation of following PK parameters ofavelumab and axitinib:Predose concentration during multiple dosing (Ctrough); andMaximum observed concentration (Cmax)

Blood samples (3.5 mL) for avelumab PK were collected in all patients: predose and at theend of infusion (immediately before the end of avelumab infusion) on Day 1 of Cycle 1, 2, 3
and 4. After that, trough (predose) samples were collected at Cycles 6 and 8 and then every
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4 cycles, ie, every 8 weeks thereafter until Cycle 24. Predose samples could have be taken
up to 2 hours prior to the start of avelumab infusion.
Blood samples for axitinib (3 mL) were collected at predose and 2 hours postdose on Day 1
of Cycle 1, Cycle 2 and Cycle 3.
PK blood samples were assayed for avelumab and axitinib using validated analyticalmethods.
Pharmacodynamics
Blood samples for pharmacodynamic evaluations were collected at Day 1 of Cycle 1, 2, 3, 4,
and 6 and the EOT/withdrawal visit enabled investigation of potential mechanisms ofresistance to the drug combination. Mandatory archival or de novo formalin-fixed andparaffin-embedded tumor tissue were collected at the time of screening.
Archived tumor tissue samples and de novo biopsies of primary and/or metastatic lesions
were used to analyze the programmed death Ligand 1 (PD-L1) and CD8.
Immunogenicity
One blood sample (3.5 mL) for anti-avelumab antibodies was collected into a serum
separator tube to provide the serum for the evaluation of avelumab immunogenicity at
predose on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 and then every 4 cycles until Cycle 32, ie,every 8 weeks thereafter until Cycle 32.
The immunogenicity blood samples were assayed for anti-avelumab antibodies using avalidated analytical method. All of the samples that were positive for anti-drug
antibodies (ADA) might have also undergone characterization for neutralizing
antibodies (nAbs).
Safety Evaluations: Safety assessments consisted of the collection of adverse events (AEs),serious adverse events (SAEs), vital signs, physical examination, 12-leadelectrocardiograms (ECGs), left ventricular ejection fraction (LVEF), laboratory
assessments, including pregnancy tests.
Safety was monitored at regular intervals throughout, and the AEs were recorded at each visit
in the study.
Statistical Methods:
Efficacy
The efficacy endpoints, objective response (OR), disease control (DC), duration of
response (DR), time to tumor response (TTR), time to progression (TTP), progression-freesurvival (PFS) and overall survival (OS) analyses were based on the full analysis set (FAS)PFIZER CONFIDENTIAL
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by treatment group. FAS included all patients who received at least 1 dose of study drug.
Assessment of response was made using RECIST v1.1. Tumor-related endpoints wereanalyzed separately based on investigator assessment and blinded independent central
review (BICR) assessment.
Best Overall Response and Objective Response
Best overall response was assessed based on reported overall lesion responses at different
evaluation time points from the first dose of study treatment until the first documentation ofPD, according to the following rules. Only tumor assessments performed on or before thestart date of any further anti-cancer therapies were considered in the assessment of best
overall response. Clinical deterioration was not to be considered as documentation of diseaseprogression.
The OR was defined as complete response (CR) or partial response (PR) according to
RECIST v1.1 from the date of first dose of study treatment until the date of the first
documentation of progression of disease. Both CR and PR was confirmed by repeat
assessments performed at least 4 weeks apart after the criteria for response were first met.
The OR rate by treatment group was also calculated along with the 2-sided 95% confidence
interval (CI) using the Clopper-Pearson method.
Disease Control
The DC was defined as CR, PR, non-CR/non-PD or stable disease. Criteria for stable disease
and non-CR/non-PD were met at least 8 weeks after date of first dose of study treatment. DC
rate was summarized by frequency counts and percentages.
Duration of Response
The DR was defined, for patients with an OR, as the time from the first documentation of OR(CR or PR) to the date of first documentation of PD or death due to any cause.
If a patient has not had an event (PD or death), DR was censored at the date of last adequate
tumor assessment. DR was displayed graphically and analyzed using Kaplan-Meiermethodology. Kaplan-Meier estimates (product-limit estimates) were presented by treatmentgroup together with a summary of associated statistics including the median DR time with
2 sided 95% CIs. If the number of patients with OR was small, the Kaplan-Meier method
could not provide reliable estimates. In this case, only descriptive statistics or listings were
provided.
Time to Response
The TTR was defined, for patients with an OR, as the time from the date of first dose of
study treatment to the first documentation of OR (CR or PR) which was subsequently
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confirmed. TTR was summarized using simple descriptive statistics (mean, standard
deviation [SD], median, minimum, maximum, first quartile [Q1] and third quartile [Q3]).
Time to Progression
TTP was defined as the time from the date of first dose of study treatment to the date of thefirst documentation of progression of disease.
TTP data were censored on the date the last adequate tumor assessment for patients withoutPD, for patients who started new anti-cancer therapy prior to PD, for patients who diedwithout PD, or for patients with PD after 2 missing tumor assessments. Patients who did
not have a baseline tumor assessment or who did not have any post-baseline tumor
assessments were censored on the date of first dose of study treatment.
Kaplan-Meier estimates (product-limit estimates) were presented by treatment group together
with a summary of associated statistics including the median TTP time with 2-sided
95% CIs.
Progression-Free Survival
PFS was defined as the time from the date of first dose of study treatment to the date of thefirst documentation of progression of disease or death due to any cause, whichever occurred
first.
PFS data were censored on the date of the last adequate tumor assessment for patients who
did not have an event (PD or death), for patients who started a new anti-cancer therapy prior
to an event or for patients with an event after 2 missing tumor assessments. Patients who
did not have an adequate baseline tumor assessment or who did not have an adequate
post-baseline tumor assessment were censored on the date of first dose of study treatment
unless death occurred on or before the time of the second planned tumor assessment(ie, ≤16 weeks after date of first dose of study treatment) in which case the death wasconsidered an event.
Kaplan-Meier estimates (product-limit estimates) were presented by treatment group together
with a summary of associated statistics including the median PFS time with 2-sided 95% CIs.
Overall Survival
The OS was defined as the time from the date of first dose of study treatment to the date ofdeath due to any cause. Patients who were last known to be alive, were censored at date oflast contact. Kaplan-Meier estimates (product-limit estimates) were presented by treatmentgroup together with a summary of associated statistics including the median OS time with
2-sided 95% CIs.

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Subset Analysis
Subset analyses using PD-L1 status (thresholds were <1%/≥1% and <10%/≥10%) at baseline
were performed for OR and PFS as per investigator assessment and BICR assessment basedon RECIST v1.1, and for OS, based on the FAS.
Pharmacokinetics
PK concentration analysis set: The PK concentration analysis set was a subset of the safety
analysis set and included patients who had at least 1 postdose concentration measurement
above the lower limit of quantitation for avelumab or axitinib.
PK parameter analysis set: The PK parameter analysis set was a subset of the safety analysis
set and included patients who had at least 1 of the PK parameters of interest for avelumab or
axitinib.
The following PK analyses were based on the PK analyses set by treatment group.
Ctrough and Cmax for avelumab and axitinib were summarized descriptively (n, mean, SD,coefficient of variation [CV], median, minimum, maximum, geometric mean, its associatedCV, and 95% CI) by treatment group, cycle, and day.
PK parameters for avelumab and axitinib were taken from observed values or derived fromconcentration-time data.
Pharmacodynamics
Biomarker data were summarized based on the biomarker analysis set by treatment group.
The biomarker analysis set for biomarkers that were measured only at screening was a subsetof the safety analysis set and included patients who had at least 1 screening biomarker
assessment.
The data were summarized at all time points described below:
Archived tumor biospecimens and de novo tumor biopsy: Screening.



Banked blood biospecimens: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4
Day 1 and Cycle 6 Day 1.

Summary statistics, using descriptive statistics (mean, SD, median, Q1, Q3, minimum, andmaximum), at each time point, ratio to screening and percent change from the value at
Screening/Cycle 1 Day 1 if available (for continuous markers) were provided by treatmentgroup.
Some biomarker analyses of tumor and blood specimens are reported separately.

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Immunogenicity
Immunogenicity data were summarized based on the immunogenicity analysis set bytreatment group. The immunogenicity analysis set was a subset of the safety analysis set andincluded patients who had at least 1 ADA/nAb sample collected for avelumab.
SafetyThe safety analysis set was the primary population for safety evaluations. It included all
patients who received at least 1 dose of study drug. Summaries of AEs and other safetyparameters were based on the safety analysis set by treatment group.
Laboratory results were classified according to the National Cancer Institute - Common
Terminology Criteria for Adverse Events criteria Version 4.03. Quantitative data weresummarized descriptively.
The other safety evaluation parameters ie, vital signs, ECGs, LVEF, physical examinationand Eastern Cooperative Oncology Group performance status were summarized descriptively
in the study.
All analyses were carried out as detailed earlier, except for summarizing by treatment groupsince there was only 1 treatment group in this study.
RESULTS
Patient Disposition and Demography:
The patient disposition for avelumab and axitinib is provided in Table S3 and Table S4,
respectively. A total of 22 patients were enrolled in the study and all patients discontinued
the study treatments. The primary reason for discontinuation of avelumab and axitinib was
PD. One patient discontinued axitinib due to AE, and then, discontinued avelumab due toPD.
Note: Group A refers to the study treatment “Avelumab 10 mg/kg + Axitinib 5 mg”.

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Table S3. Patient Disposition for Avelumab at End of Treatment - Full Analysis Set
Number of Patients

Group A
(N=22)
n (%)

Disposition phase: end of treatment
Discontinued
22 (100.0)
Reason for discontinuation
Adverse event
2 (9.1)
Progressive disease
18 (81.8)
Withdrawal by patient
2 (9.1)
Ongoing0
The denominator to calculate percentages is N, the number of patients in the full analysis set within eachtreatment group.

Table S4. Patient Disposition for Axitinib at End of Treatment - Full Analysis Set
Number of Patients

Group A
(N=22)
n (%)

Disposition phase: end of treatment
Discontinued
22 (100.0)
Reason for discontinuation
Adverse event
3 (13.6)
Progressive disease
17 (77.3)
Withdrawal by patient
2 (9.1)
Ongoing0
The denominator to calculate percentages is N, the number of patients in the full analysis set within eachtreatment group.

A total of 22 Japanese patients (20 male [90.9%] and 2 female [9.1%]) were included in the
study. The median age (range) of patients was 68.5 (20-84) years. The median time from theinitial diagnosis of HCC to the date of first dose of study treatment was 16.59 months. The
median time from diagnosis of recurrent/metastatic disease to the date of first dose of study
treatment was 2.42 months.
The majority of patients (17 of 20) had PD-L1 positive tumors at the 1% cutoff defined as
PD-L1 staining of any intensity in tumor-associated immune cells (ICs) and tumor cells(TCs) covering ≥1% of tumor area.

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Efficacy Results:
Best Overall Response and Objective Response
ORs (ie, CR + PR) were observed in 3 patients (13.6% [95% CI: 2.9, 34.9]) per investigatorassessment.
DC (ie, CR + PR + stable disease + non-CR/non-PD) was observed in 15 patients (68.2%[95% CI: 45.1, 86.1]) per investigator assessment (RECIST v1.1). Fifteen of 21 treatedpatients with target lesions and a post-baseline tumor assessment had at least some degree oftumor shrinkage in the target lesions during the study.
As per BICR assessment, OR was observed in 1 patient (4.5% [95% CI: 0.1, 22.8]) and
DC was observed in 15 patients (68.2% [95% CI: 45.1, 86.1]).
Time to Tumor Response and Duration of Response
The median TTR observed for avelumab in combination with axitinib was 1.91 months(range: 1.9, 3.7). The median DR using Kaplan-Meier estimates (RECIST v1.1) was
7.29 months (95% CI: 3.71, 12.94).
Time to Progression
The results of TTP showed that at the time of data cutoff, 21 patients (95.5%) had an
event (PD) for the analysis of TTP. The median TTP using Kaplan-Meier estimates(RECIST v1.1) was 5.52 months (95% CI: 1.91, 7.39).
Progression-Free Survival
The PFS results per investigator assessment (RECIST v1.1) showed that at the time of data
cutoff, 21 patients (95.5%) had an event (PD or death) for the analysis of PFS. The median
PFS was 5.52 months (95% CI: 1.91, 7.39), and the PFS rates at 6 and 12 months were
38.1% (95% CI: 18.3, 57.8) and 9.5% (95% CI: 1.6, 26.1), respectively.
The median duration of follow-up for PFS based on investigator assessment was notapplicable (NA) (95% CI: NA, NA), estimated using reverse Kaplan-Meier method.
As per BICR assessment, median PFS was 5.55 months (95% CI: 2.79, 9.33). The PFS rates
at 6 and 12 months were 46.4% (95% CI: 24.4, 65.9) and 18.6% (95% CI: 3.9, 41.7),
respectively. The median duration of follow-up for PFS based on BICR assessment was
11.07 months (95% CI: 5.55, 14.65), estimated using reverse Kaplan-Meier method.

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Overall Survival
The results of OS showed that at the time of data cutoff, 12 patients (54.5%) had an event(death) for the analysis of OS. The median OS was 14.05 months (95% CI: 7.95, NA) andOS rate at 12 months was 54.5% (95% CI: 32.1, 72.4).
The median duration of follow-up for OS was 23.23 months (95% CI: 20.34, 23.95),
estimated using reverse Kaplan-Meier method.
Subset Analysis by Patients With PD-L1-Positive and PD-L1-Negative Tumors
Objective Response and Disease Control
In the IC + TC combined group, results of OR and DC evaluation were as follows:
Based on the investigator assessment (RECIST v1.1), the OR for patients with
PD-L1-positive and PD-L1-negative tumors at the 1% cutoff was observed in
3 patients (17.6% [95% CI: 3.8, 43.4]), and no patient (95% CI: 0.0, 70.8), respectively.
The DC for patients with PD-L1-positive versus PD-L1-negative tumors at the 1% cutoff wasobserved in 13 patients (76.5% [95% CI: 50.1, 93.2]), and 1 patient (33.3% [95% CI: 0.8,90.6]), respectively.
Progression-Free Survival
In the IC + TC combined group, results of PFS evaluation were as follows:
Based on the investigator assessment (RECIST v1.1), the Kaplan-Meier estimate of median
PFS for patients (95% CI) with PD-L1-positive versus PD-L1-negative tumors at the 1%
cutoff was 5.55 months (1.91, 9.17) and 5.49 months (1.77, 9.20), respectively. The
probability of being event-free for PFS (95% CI) at 6 months for patients with
PD-L1-positive tumors at the 1% cutoff was 41.2% (18.6, 62.6), and was 50.0% (0.6, 91.0)
for PD-L1-negative tumors. The probability of being event-free for PFS (95% CI) at
12 months for patients with PD-L1-positive tumors at the 1% cutoff was 11.8% (2.0, 31.2),
and was not applicable for PD-L1-negative tumors.
Overall Survival
In the IC + TC combined group, the Kaplan-Meier estimate of median OS for patients (95%
CI) with PD-L1-positive versus PD-L1-negative tumors at the 1% cutoff was NA (8.71, NA),and 7.95 months (6.05, NA) respectively. The probability of being event-free (95% CI) for
OS at 12 months for patients with PD-L1-positive tumors at the 1% cutoff was 64.7% (37.7,
82.3) and was 33.3% (0.9, 77.4) for PD-L1-negative tumors.

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Pharmacokinetic, Pharmacodynamic and Immunogenicity Results:
Pharmacokinetics
Avelumab serum concentrations appeared to reach steady state at Cycle 2. After Cycle 2
Day 1, avelumab Ctrough concentrations trended slightly upward upto Cycle 28 Day 1.
However, the variability in mean Ctrough ranged from 19% to 51%, with mostly overlapping
distribution of concentration over time. Therefore, the interpretation of the time dependency
in Ctrough was limited due to a decrease in sample size over time.
Mean and median axitinib plasma Ctrough concentrations remained stable on Cycle 2 Day 1
and Cycle 3 Day 1, in the presence of avelumab.
Mean and median axitinib plasma Cmax concentrations also remained stable on Cycle 1
Day 1, Cycle 2 Day 1, and Cycle 3 Day 1, in the presence of avelumab. The variability inmean Ctrough and Cmax ranged from 73% to 106%, with overlapping distribution ofconcentration over time. This indicated that axitinib exposure was not affected by theadministration of avelumab on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1.
Pharmacodynamics
Biomarkers in the study included PD-L1 status and CD8+ cells.
For the PD-L1 target, the median (range) of IC% was 2.50% (0.0, 15.0). The majority (17 of20) of patients had PD-L1-positive tumors at the 1% cutoff defined as PD-L1 staining of any
intensity in tumor-associated ICs and TCs covering 1% of tumor area.
The median (range) of CD8+ cells invasive margin (%) and CD8+ cells total area (%) were
2.06% (0.2, 5.4) and 0.55% (0.1, 5.9), respectively.
Immunogenicity
There were low incidences of ADA reported in the study. Three patients (13.6%) werereported as ADA ever-positive. Treatment-induced ADA response was observed in
3 patients (13.6%); with all having persistent ADA response (3 patients [13.6%]).
The median duration of time to ADA response was 10.14 weeks (range: 4.00-14.14). A
Kaplan-Meier plot of duration of ADA response showed that out of the 3 patients withtreatment-induced ADA, the median duration of ADA response was 8.14 weeks(95% CI: 4.57, 9.14).
Three patients (13.6%) were reported as nAb ever-positive. The median duration of time tonAb response was 10.14 weeks (range: 8.43-14.14). A Kaplan-Meier plot of duration of nAb
showed that out of the 3 patients with treatment-induced nAb, the median duration of nAb
response was 8.14 weeks (95% CI: 0.14, 9.14).
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The interpretation of the ADA impact on avelumab PK was very limited due to the small
number of treatment-induced ADA-positive patients (n=3) compared to ADA never-positive
or baseline ADA positive patients (n=19).
Safety Results:
Treatment-Emergent Adverse Events
All patients in the study experienced at least 1 treatment-emergent adverse event (TEAE).
Twenty-one patients (95.5%) experienced treatment-related TEAEs.
Seventeen patients (77.3%) reported Grade ≥3 TEAEs, which were treatment-related in
16 patients (72.7%). Discontinuation of all study drugs due to TEAEs was reported in
2 patients (9.1%) and was not due to treatment-related TEAEs.
The all-causality and treatment-related TEAEs that occurred in ≥20% of patients andGrade ≥3 TEAEs that occurred in ≥5% patients are presented by SOC and PT in Table S5.
The most common all-causality (TEAEs) reported in ≥20% of patients wereHypertension (17 patients [77.3%]), Decreased appetite (12 patients [54.5%]), Dysphonia
and Palmar-plantar erythrodysaesthesia syndrome (11 patients [50.0%] each), Stomatitis andWeight decreased (9 patients [40.9%] each), Hypothyroidism, Constipation andMalaise (7 patients [31.8%] each), Diarrhea, Pyrexia, Dysgeusia, Proteinuria and Rash
(6 patients [27.3%] each). The most common Grade ≥3 TEAEs reported in ≥5% of patientswere Hypertension (11 patients [50.0%]), Palmar-plantar erythrodysaesthesia
syndrome (5 patients [22.7%]), Decreased appetite (3 patients [13.6%]), Stomatitis andFatigue (2 patients [9.1%] each).
The most common treatment-related TEAEs reported in ≥20% of patients wereHypertension (17 patients [77.3%]), Decreased appetite (12 patients [54.5%]), Dysphonia
and Palmar-plantar erythrodysaesthesia syndrome (11 patients [50.0%] each), Stomatitis(9 patients [40.9%]), Weight decreased, Hypothyroidism and Malaise(7 patients [31.8%] each), Diarrhea, Dysgeusia, Proteinuria and Rash (6 patients [27.3%]each). The most common Grade ≥3 treatment-related TEAEs reported in ≥5% of patientswere Hypertension (11 patients [50.0%]), Palmar-plantar erythrodysaesthesia syndrome(5 patients [22.7%]), Decreased appetite (3 patients [13.6%]), Stomatitis and Fatigue(2 patients [9.1%] each).
Due to the very limited number of ADA positive patients (n=3) compared to ADA negative
patients (n=19), potential effect of ADA on safety was not evaluated appropriately. Under
such a limited condition, no clinically meaningful impact of ADA on the safety profile was
identified. The percentage of patients reporting TEAEs was same for ADA never-positive
patients and ADA ever-positive patients (100% and 100%, respectively).

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The percentage of patients reporting TEAEs for treatment-induced ADA was same for ADA
never-positive or baseline ADA positive patients (100% and 100%, respectively).

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Table S5. Most Common Treatment-Emergent Adverse Events (Any Gradein ≥20% Patients or Grade 3 in ≥5% Patients) by System Organ Classand Preferred Term - Safety Analysis Set
System Organ Class andPreferred Term

Group A
(N=22)All TEAEsn (%)

Related
TEAEs
n (%)

Grade ≥3
TEAEs
n (%)

Related
Grade ≥3
TEAEs
n (%)
16 (72.7)005 (22.7)
01 (4.5)2 (9.1)2 (9.1)

Patients with events
22 (100.0)
21 (95.5)
17 (77.3)
Endocrine disorders
8 (36.4)
8 (36.4)
0
Hypothyroidism
7 (31.8)
7 (31.8)
0Gastrointestinal disorders
18 (81.8)
14 (63.6)
5 (22.7)
Constipation
7 (31.8)00Diarrhoea
6 (27.3)
6 (27.3)
1 (4.5)
Stomatitis
9 (40.9)9 (40.9)2 (9.1)
General disorders and administration
15 (68.2)
11 (50.0)
2 (9.1)
site conditions
Fatigue
3 (13.6)
3 (13.6)2 (9.1)2 (9.1)
Malaise7 (31.8)
7 (31.8)
00
Pyrexia
6 (27.3)
1 (4.5)00Investigations
13 (59.1)
12 (54.5)
2 (9.1)1 (4.5)Weight decreased
9 (40.9)
7 (31.8)00Metabolism and nutrition disorders
12 (54.5)
12 (54.5)
3 (13.6)
3 (13.6)
Decreased appetite
12 (54.5)
12 (54.5)
3 (13.6)
3 (13.6)
Nervous system disorders
8 (36.4)
7 (31.8)
1 (4.5)1 (4.5)Dysgeusia
6 (27.3)
6 (27.3)
00Renal and urinary disorders
6 (27.3)
6 (27.3)
1 (4.5)1 (4.5)
Proteinuria
6 (27.3)
6 (27.3)
1 (4.5)1 (4.5)
Respiratory, thoracic and mediastinal
13 (59.1)
11 (50.0)
00disorders
Dysphonia
11 (50.0)
11 (50.0)00Skin and subcutaneous tissue
15 (68.2)
15 (68.2)
5 (22.7)
5 (22.7)
disorders
Palmar-plantar erythrodysaesthesia
11 (50.0)
11 (50.0)
5 (22.7)
5 (22.7)
syndromeRash
6 (27.3)
6 (27.3)
00
Vascular disorders
17 (77.3)
17 (77.3)
11 (50.0)
11 (50.0)
Hypertension
17 (77.3)
17 (77.3)
11 (50.0)
11 (50.0)
The denominator to calculate percentages is N, the number of patients in the safety analysis set within eachtreatment group.
Patients reporting >1 TEAE within a preferred term were counted only once in that preferred term.
Patients reporting multiple preferred terms within the same SOC were counted only once within each SOC.
Treatment-related TEAEs include TEAEs related to at least 1 study drug in the combination.
MedDRA Version 22.1 coding dictionary and CTCAE Version 4.03 applied.
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; MedDRA=Medical
Dictionary for Regulatory Activities; SOC=system organ class; TEAE=treatment-emergent adverse event.

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Permanent Discontinuations due to Adverse Events
Out of the 3 patients (13.6%) who discontinued any study drug due to TEAEs,
1 patient (4.5%) discontinued due to a TEAE (diverticulum intestinal haemorrhagic)
considered related to study treatment. Discontinuation of all study drugs due to TEAEs wasreported in 2 patients (9.1%) and was not due to treatment-related TEAEs.
Dose Reductions or Temporary Discontinuations due to Adverse Events
Eight patients (36.4%) reported TEAEs leading to interruption of avelumab, and14 patients (63.6%) reported TEAEs leading to interruption of axitinib. The dose of axitinib
was reduced for 13 patients (59.1%). Avelumab dose reductions were not permitted byprotocol, and no TEAEs resulted in dose reduction of avelumab.
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
Deaths
A total of 12 patients (54.5%) died in the study, and the most common cause of death was
disease progression (11 patients [50.0%]). One patient died due to an unknown cause. No
patient died within 30 days after the last dose of study treatment, and no TEAEs leading todeath were reported in the study. No patient died due to study treatment toxicity.
Other Serious Adverse Events
SAEs were reported in 8 patients (36.4%), of which SAEs reported in 6 patients (27.3%)
were considered to be treatment-related.
Other Significant Adverse Events
Immune-Related Adverse Events
A total of 10 patients (45.5%) reported irAEs in the study which included hypothyroidism(7 patients [31.8%]), hyperthyroidism (3 patients [13.6%]), adrenal insufficiency, pruritus
and rash (2 patients [9.1%] each), thyroiditis chronic and rash maculo-popular(1 patient [4.5%] each). No serious, Grade ≥3 irAEs and irAEs leading to death werereported in the study. No discontinuations of study drug (avelumab/axitinib) due to irAEs
were reported in the study.
Infusion-Related Reactions
A total of 3 patients (13.6%) reported infusion-related reactions (IRR) events in the study
which included chills in 1 patient (4.5%) and infusion related reaction in 2 patients (9.1%).
No serious, Grade ≥3 IRRs and IRRs leading to death were reported in the study. No

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discontinuations of study drug (avelumab/axitinib) due to IRRs were reported in the study.
The IRRs occurred at the first infusion in the study and were Grade 1 or Grade 2.
Laboratory Evaluations and Other Parameters Related to Safety
The most common Grade 1-4 hematology abnormal values included anemia and platelet
count decreased (reported in 16 patients [72.7%] each) followed by lymphocyte countdecreased (14 patients [63.6%]). Grade 3 hematology abnormal values included lymphocyte
count decreased, reported in 1 patient (4.5%). There were no Grade 4 hematology laboratory
values.
In the chemistry laboratory evaluations, the most common Grade 3 abnormal values included
gamma glutamyl transferase increased, reported in 7 patients (31.8%) followed by alkaline
phosphatase increased, reported in 3 patients (13.6%).
The Grade 4 chemistry laboratory values included cholesterol high and hypokalemia,
reported in 1 patient (4.5%) each.
For the liver function tests, no potential Hy's law cases were observed in the study.
No clinically significant ECG abnormalities were observed during the study.
Conclusions:

The safety profile of avelumab 10 mg/kg Q2W with axitinib 5 mg BID as first line
treatment in patients with advanced HCC was manageable, tolerated, and consistent withthe known safety profiles of avelumab and axitinib as single agents.



The antitumor activity of avelumab in combination with axitinib as first line treatment
was observed in patients with advanced HCC per RECIST v1.1.



The majority (17 of 20) of patients had PD-L1-positive tumors at the 1% cutoff definedas PD-L1 staining of any intensity in tumor-associated ICs and TCs covering 1% of
tumor area. The interpretation is limited due to the small number of patients with
PD-L1-negative tumors. There was no meaningful difference in the proportion ofpatients achieving OR and PFS for patients with PD-L1-positive versus PD-L1-negative
tumors at the 1% cutoff. Longer OS was more likely to be observed in patients with
PD-L1-positive tumors than in patients with PD-L1-negative tumors.



Avelumab serum concentrations appeared to reach steady state at Cycle 2 and appeared
to increase slightly over time, however, the interpretation of the time dependency inavelumab serum concentrations is limited due to a decrease in sample size over time andrelatively moderate to large variability. Axitinib exposure was not affected by theadministration of avelumab on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1.

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The interpretation of the ADA impact on avelumab PK is very limited due to the small
number of treatment-induced ADA-positive patients (n=3) compared to ADA
never-positive or baseline ADA positive patients (n=19). ADA did not appear to impact
the safety of the combination treatment, however, interpretation of the ADA impact on
the safety is also very limited.

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