Abbreviated Clinical Study Report
Protocol B9991009

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Inc.
Investigational Product: MSB0010718C
Clinical Study Report Synopsis: Protocol B9991009
Protocol Title: A Phase 3, Multicenter, Randomized, Open-Label Study of Avelumab(MSB0010718C) Alone or in Combination With Pegylated Liposomal Doxorubicin Versus
Pegylated Liposomal Doxorubicin Alone in Patients With Platinum Resistant/Refractory
Ovarian Cancer
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Centers: 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: 21 December 2015
Primary Completion Date: 19 September 2018
Report Date: 30 April 2019
Previous Report Date(s): Not applicable
Phase of Development: Phase 3
Primary and Secondary Study Objectives and Endpoints: The primary and secondary
objectives and endpoints are outlined in Table 1.

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Abbreviated Clinical Study Report
Protocol B9991009

CLINICAL STUDY REPORT SYNOPSIS
Table 1.

Primary and Secondary Study Objectives and Endpoints

Type
Primary
Efficacy

ObjectiveSecondary
EfficacyEndpointOS

PFS as determined by BICR
according to RECIST version 1.1

To evaluate anti-tumor activity ofavelumab given alone or in combination
with PLD versus PLD alone in ovariancancer patients.



PFS as determined by investigatoraccording to RECIST version 1.1
OR, DR, and DC as determinedby BICR and Investigator (asassessed by RECIST version 1.1)
AEs (as graded by NCI CTCAE
version 4.03); laboratory
abnormalities (as graded by NCI
CTCAE version 4.03); vital signs(BP and pulse rate); ECGs,
ECHO or MUGA scans
PK parameters, including Ctroughand Cmax for avelumab, Cmax, Vd,
CL, and AUC for doxorubicin(PLD samples)

To demonstrate that avelumab given alone
or in combination with PLD is superior to
PLD alone in prolonging OS in patientswithplatinum-resistant/platinum-refractory
ovarian cancer.
To demonstrate that avelumab given alone
or in combination with PLD is superior to
PLD alone in prolonging PFS in patientswithplatinum-resistant/platinum-refractory
ovarian cancer.

Safety

To evaluate the overall safety profile ofavelumab alone or in combination with
PLD versus PLD alone in ovarian cancer
patients.

PK(None Reported)Immunogenicity(None Reported)
Biomarker



PRO



To characterize the PK of doxorubicin(PLD samples) and avelumab whenadministered in combination, and to assess
the effect of avelumab on the PK of
doxorubicin (PLD sample) and the effectof PLD on PK of avelumab.
To assess the immunogenicity ofavelumab.
To evaluate candidate predictive
biomarkers of sensitivity or resistance toavelumab or PLD in combination withavelumab in pre-treatment tumor tissue,that may aid in the identification of patient
subpopulations most likely to benefit fromtreatment.
To compare the effect of avelumab alone
or in combination with PLD versus PLD
alone on PRO in patients with ovariancancer.



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Incidence of ADA and nAbagainst avelumab
Candidate predictive biomarkers
in tumor tissue including, but notlimited to, PD-L1 expression andtumor infiltrating CD8+ T
lymphocytes as assessed by IHC
Ovarian cancer specificdisease/treatment-related
symptoms as measured by
EORTC QLQ-C30, EORTCQLQ-OV28, and EQ-5D-5L

Abbreviated Clinical Study Report
Protocol B9991009

CLINICAL STUDY REPORT SYNOPSISMETHODS
Study Design: This was a Phase 3, multicenter, randomized, open-label, parallel 3-arm
study in which approximately 550 patients who met the eligibility criteria were planned to berandomized in a 1:1:1 ratio to receive avelumab alone, avelumab in combination with
pegylated liposomal doxorubicin (PLD), or PLD alone as follows:

Arm A (Experimental, Avelumab Alone): Avelumab 10 mg/kg given as a 1-hour
intravenous (IV) infusion every 2 weeks (Q2W);



Arm B (Experimental, Avelumab + PLD): Avelumab 10 mg/kg given as a 1-hour IV
Q2W + PLD 40 mg/m2 given as a 1-hour IV infusion every 4 weeks (Q4W);

Arm C (Control, PLD Alone): PLD 40 mg/m2 given as a 1-hour IV infusion Q4W.

Patients were stratified by platinum-refractory or platinum-resistant status, number of priorregimens (1 versus 2 or 3), and bulky disease (defined as presence of a tumor ≥5 cm) versus
not. Cross-over was not permitted.
The study included up to 4 periods:


Screening: Up to 28 days before randomization,Study treatment: Treatment following randomization,

Short-term follow-up: Follow-up for 90 days after the last dose of study (hereafterreferred to as follow-up),Long-term follow-up: Follow-up until death, End of Study, or withdrawal of consent,
whichever occurred first.

Patients might have withdrawn from treatment at any time at their own request, or they might
have been withdrawn at any time at the discretion of the investigator or sponsor for safety or
behavioral reasons, or the inability of the patient to comply with the protocol requiredschedule of study visits or procedures at a given study site.
The final analysis of this study has been completed; however, this study remains open to
allow the remaining patients currently enrolled in the Arm A or Arm B to continue receiving
avelumab as a single-agent or in combination with PLD. These patients will be allowed tocontinue receiving avelumab based on the investigator’s assessment that the anticipatedbenefit outweighs the risks.
Diagnosis and Main Criteria for Inclusion: Eligible patients were adult patients(18 years of age or 20 years of age in Japan) with histologically confirmed epithelial
ovarian, fallopian tube, or primary peritoneal cancer and who had platinum-resistant or
platinum-refractory disease. Eastern Cooperative Oncology Group (ECOG) performance
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Abbreviated Clinical Study Report
Protocol B9991009

CLINICAL STUDY REPORT SYNOPSIS
status was required to be 0 to 1. Patients may have received up to 3 prior lines of systemic
anticancer therapy for platinum-sensitive disease, a platinum containing regimen was
required as their most recent therapy and no prior systemic therapy for platinum-resistantdisease was allowed. Patients were required to have measurable disease by Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with at least 1 unidimensional
measurable lesion that had not previously been irradiated.
Study Treatment: Study drugs were administered by IV infusion. In the combination arm,
PLD was administered on Day 1 of each cycle and on that day it was administered first
before the avelumab infusion. Refer to Table 2 for a list of study drug information involvedin this study.
Table 2.

Investigational Product Description

Investigational Product Description
MSB0010718C solution for infusion, 20 mg/mL(10 mL/vial)
MSB0010718C solution for infusion, 20 mg/mL(10 mL/vial)
MSB0010718C solution for infusion, 20 mg/mL(10 mL/vial)
MSB0010718C solution for infusion, 20 mg/mL(10 mL/vial)
Doxorubicin HCl liposome injection 20 mg/10mL
vial in 1x1 carton
Doxorubicin HCl liposome injection 20 mg/10mL
vial in 1x1 carton
Doxorubicin HCl liposome injection 20 mg/10mL
vial in 1x1 carton
Doxorubicin HCl liposome injection 20 mg/10mL
vial in 1x1 carton
Doxorubicin HCl liposome injection 20 mg/10mL
vial in 1x1 carton
Doxorubicin HCl liposome injection 20 mg/10mL
vial in 1x1 carton
Doxorubicin HCl liposome injection 20 mg/10ml
vial in 1x1 carton
Doxorubicin HCl liposome injection 20 mg/10ml
vial in 1x1 carton
Pegylated liposomal doxorubicin HCl
20 mg/10mL vial for infusion in 1x1 carton
Pegylated liposomal doxorubicin HCl
20 mg/10mL vial for infusion in 1x1 carton
Pegylated liposomal doxorubicin HCl 20 mg/10ml
vial for infusion in 1x1 carton
Pegylated liposomal doxorubicin HCl
20 mg/10mL vial for infusion in 1x1 carton

Vendor Lot
Number

Pfizer Lot
NumberStrength/
Potency

DosageForm

PD1F006

15-006071

200 mgsolution

PD1F01116-000913

200 mgsolution

PD1E002

15-002315

200 mgsolution

PD1G001

16-000917

200 mg

DCXIA1535

15-007727

2 mg/ml

600220P1

16-001733

2 mg/ml

600520P1

17-000459

2 mg/ml

600520P1

17-000540

2 mg/ml

DCXIA1559

16-002754

2 mg/ml

DCXIA1557

16-002518

2 mg/ml

600920P1

17-001570

2 mg/mlHCZTK01

18-000181

2 mg/mlFAZSR00

15-005744

2 mg/mlFBZT600

15-005845

2 mg/mlFAZSR00

15-005390

2 mg/ml

FEZSZ00

15-006456

2 mg/mlsolutioncommercial
product
commercial
product
commercial
product
commercial
product
commercial
product
commercial
product
commercial
product
commercial
product
commercial
product
commercial
product
commercial
product
commercial
product

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Abbreviated Clinical Study Report
Protocol B9991009

CLINICAL STUDY REPORT SYNOPSIS
Efficacy Evaluations: The primary and secondary efficacies are reported out as outlined inTable 3.
As of the data cut-off date (19 September 2018), anti-tumor activities were assessed throughradiological tumor assessments conducted at baseline (screening) and every 8 weeks
thereafter until documented disease progression as assessed by Blinded Independent Central
Review (BICR). Radiological tumor assessments were also conducted whenever diseaseprogression was suspected (eg, symptomatic deterioration) and at the time of withdrawal
from the treatment (if not done in the previous 4 weeks). Complete, partial responses (CR,PR) and progressive disease were confirmed on repeated imaging 4 weeks after initial
documentation.
The Patient Report Outcome (PRO) questionnaires were administered on the first day of eachtreatment cycle as well as upon End of Treatment (EOT)/Study Withdrawal and Post
Treatment Safety Follow-up (Days 30, 60 and 90).

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Abbreviated Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS
Table 3.

Efficacy Evaluations

Evaluation
PrimaryOS
PFS as determinedby BICR

Definition
Time from the date of randomization to the date of death due to any cause.
Patients last known to be alive were censored at date of last contact.
Time from randomization to the date of the first documentation of progression of
disease as determined by BICR according to RECIST version 1.1, or death due toany cause, whichever occurs first.
PFS data were censored on the date of the last adequate tumor assessment forpatients who did not have an event (disease progression or death), for patients whostarted a new anti-cancer therapy prior to an event or for patients with an event after
2 or more 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 randomization unless death occurred on or
before the time of the second planned tumor assessment (ie, ≤16 weeks after thedate of randomization) in which case the death was considered an event.

Secondary
PFS as determinedby investigator

OR based on BICR
and investigatorassessment

Time to Response
based on BICR andinvestigatorassessment
DR based on BICR
and investigatorassessment

DC based on BICR
and investigatorassessment

Time from randomization to the date of the first documentation of progression of
disease as determined by Investigator according to RECIST version 1.1 or death due
to any cause, whichever occurs first.
Censoring algorithm is similar to PFS based on BICR assessment.
A confirmed BOR of CR or PR according to RECIST version 1.1. Both CR and PR
must be confirmed by repeat assessments performed no less than 4 weeks after thecriteria for response are first met and before the first documentation of diseaseprogression. Only tumor assessments performed on or before the start date of any
further anti-cancer therapies were considered in the assessment of BOR.
Patients who did not have a post-baseline radiographic tumor assessment due toearly progression, who received anti-tumor therapies other than the study treatments
prior to reaching a CR or PR, or who died, progressed, or dropped out for any
reason prior to reaching a CR or PR were counted as non-responders in theassessment of OR.
For patients with an OR, the time from the date of randomization to the first
documentation of OR (CR or PR) which is subsequently confirmed.
For patients with an OR per RECIST version 1.1, the time from the first
documentation of objective tumor response (a complete or partial response) to thefirst documentation of objective tumor progression or death due to any cause,
whichever occurs first.
If a patient did not have an event (PD or death), DR was censored at the date of lastadequate tumor assessment.
A BOR of CR, PR, non-complete response/non-progressive disease or stable diseaseaccording to the RECIST version 1.1.

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Abbreviated Clinical Study Report
Protocol B9991009

CLINICAL STUDY REPORT SYNOPSIS
Table 3

Efficacy Evaluations

Evaluation
PRO

Definition
EORTC QLQ-C30: a 30-question survey and includes 5 functional subscales(physical, role, emotional, cognitive, and social), QoL subscale, and symptom
subscales/items. Higher scores on the functioning/QoL subscales indicate higher
levels of functioning. Higher scores on the symptom scales/items indicate greater
presence of symptoms.
EORTC QLQ-OV28: a 28-item instrument with 7-symptom subscales; similar to
the EORTC QLQ-C30, higher scores are reflective of a greater presence ofsymptoms.
EQ-5D-5L: 2 components - a Health State Profile which has individuals rate theirlevel of problems (none, slight, moderate, severe, extreme/unable) in 5 areas(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression); and a
VAS in which patients rate their overall health status from 0 (worst imaginable) to100 (best imaginable).

Biomarker Evaluations: Programmed death ligand 1 (PD-L1) expression and tumor
infiltrating CD8 positive (CD8+) T lymphocytes as assessed by immunohistochemistry(IHC) were candidate predictive biomarkers in this study.
Safety Evaluations: Safety evaluations included clinical monitoring, vital signs, 12-leadelectrocardiogram (ECG), adverse events (AEs), physical examinations, multiple-gatedacquisition (MUGA)/echocardiogram, ECOG performance and safety laboratory tests.
Statistical Methods: the key statistical methods are briefly summarized as below.
Primary Efficacy
The primary analyses of Progression-Free Survival (PFS) were performed based on BICR
assessment using the full analysis set (FAS), which included all randomized patients. A
stratified log rank test (1-sided) stratified by randomization stratification factors was
performed. PFS time was summarized by treatment arm using the Kaplan-Meier method.
The Cox proportional hazards (PH) model was fitted to compute the hazard ratio and thecorresponding confidence interval (CI). In order to account for the group sequential designin this study, the repeated CI (RCI) method was used to construct the 2-sided RCI for thehazard ratio. A similar analysis was performed for the primary analysis of Overall Survival(OS).
Secondary Efficacy
Sensitivity Analyses: Sensitivity analyses were performed to explore the robustness ofthe primary analysis results for PFS based on BICR assessment and the primary analysis
results of OS. The sensitivity analyses repeated the primary analysis (p-value, hazard
ratio and 95% CIs) with modifications. PFS based on BICR assessment and OS werealso analyzed based on restricted mean survival time (RMST) differences.
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Abbreviated Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSISPFS Based on Investigator Assessment: repeated the analysis for the PFS based oninvestigator assessment.



The Objective Response Rate (ORR) Based on BICR and Investigator Assessments:
were estimated by dividing the number of patients with objective response (complete
response [CR] or partial response [PR]) by the number of patients randomized to therespective treatment arm. The corresponding exact 2-sided 95% CIs are provided bytreatment arm. The association of treatment and Objective Response (OR) was also
tested by the General Association Statistic of the Cochran-Mantel-Haenszel test (CMH)with the randomization strata taken into account.

Time to Response Based on BICR and Investigator Assessments: are summarized using
simple descriptive statistics.



Duration of Response (DR) Based on BICR and Investigator Assessments: aresummarized by treatment arm using Kaplan-Meier method. The median DR and 95% CI
for the median are provided for each treatment arm.



Disease Control Rate (DCR) Based on BICR and Investigator Assessments: defined as
the proportion of patients with best overall response of CR, PR, non-complete
response/non-progressive disease or stable disease (SD), was calculated for eachtreatment arm, along with 2-sided 95% CI using the Clopper-Pearson method.



Subgroup Analyses: were performed for OS, PFS based on BICR assessment, OR basedon BICR assessment and DR based on BICR assessment for the pre-specified subgroups.



PRO: descriptive summaries over time are provided for the PRO endpoints. The
treatment effect on time-to-deterioration (TTD) in patient’s European Organization for
Research and Treatment of Cancer Quality of Life Questionnaire Ovarian Cancer 28(EORTC QLQ-OV28) abdominal/gastrointestinal (GI) symptom subscale were estimatedusing a Cox’s PH model stratified by the randomization strata to calculate the hazard
ratio for the experimental arms versus control arm. Kaplan-Meier estimates(product-limit estimates) are presented by treatment arm together with a summary of
associated statistics including the median TTD time with 2-sided 95% CI.

Biomarkers: Appropriate statistical methods using biomarker analysis set was used toinvestigate any possible relationship of biomarker levels with avelumab anti-tumor
efficacy relative to appropriate control arms.

Descriptive statistics were used to summarize all patient characteristics, treatment
administration/compliance, and safety parameters. The Safety Analysis Set was the primary
population for safety evaluation, which included all patients who receive at least 1 dose of
study treatment (ie, avelumab or PLD).

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CLINICAL STUDY REPORT SYNOPSISRESULTS
Subject Disposition and Demography: A total of 566 patients were randomized (188 eachto the avelumab arm and the avelumab in combination with PLD arm, and 190 to the PLD
arm).
Of the 566 patients randomized, 546 patients received at least 1 dose of study drug (187 in
the avelumab arm, 182 in the combination arm, and 177 in the PLD arm) (Table 4). At thetime of data cutoff (19 September 2018), of the 188 patients randomized to the combination
treatment, 178 (94.7%) patients discontinued avelumab and 183 (97.3%) patients
discontinued PLD. In the avelumab arm and the PLD arm, 182 (96.8%) and 190 (100.0%)
patients discontinued from treatment, respectively (Table 4). Disease progression(progressive disease) was the primary reason for discontinuation from treatment (61.2% for
avelumab and 53.7% for PLD in the combination arm, 71.8% in the avelumab arm and49.5% in the PLD arm) (Table 4).
Patients who discontinued from treatment and did not withdraw consent continued into thefollow-up phase or directly into the long-term follow-up (if the patient initiated subsequentanti-cancer therapy at the EOT or by patient request). There were 389 patients and386 patients entering the follow-up and long-term follow-up phases, respectively. The
primary reasons for discontinuation from study during follow-up and long-term follow-up
were “other” (including start of new therapy) and “death”, respectively.

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Table 4.

MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Subject Disposition for Study Drugs at End of
Treatment - Full Analysis Set

Disposition phase: end of treatment
Discontinued
Reason for discontinuation
Death
Progressive disease
Adverse event
Non-compliance with study drug
Physician decision
No longer meets eligibility criteria
Global deterioration of health status
Withdrawal by subject
Other
Ongoing

Avelumab(N=188)Avelumabn (%)

Avelumab + PLD(N=188)Avelumab
PLD
n (%)
n (%)

PLD
(N=190)PLDn (%)

182 (96.8)

178 (94.7)

183 (97.3)

190 (100.0)

4 (2.1)135 (71.8)
16 (8.5)
1 (0.5)0
1 (0.5)19 (10.1)
4 (2.1)2 (1.1)6 (3.2)6 (3.2)115 (61.2)
29 (15.4)
02 (1.1)0
19 (10.1)
6 (3.2)1 (0.5)10 (5.3)

4 (2.1)101 (53.7)
37 (19.7)
0
16 (8.5)019 (10.1)
5 (2.7)1 (0.5)5 (2.7)5 (2.6)
94 (49.5)
21 (11.1)
0
11 (5.8)
2 (1.1)24 (12.6)
31 (16.3)
2 (1.1)0

The denominator to calculate percentages is N, the number of subjects in the full analysis set within each treatment group.
PFIZER CONFIDENTIAL SDTM Creation: 30OCT2018 (13:50) Source Data: ADDS Output File:./B999_UNBLINDED/B9991009_CSR/adds_s002d Date of Generation: 25JAN2019 (17:56)
Table 14.1.1.2.4 is for Pfizer internal use.

All enrolled patients were female, and the median age was 60 years old (range 26 to
86 years). Most of the patients were from Europe (48.8%), North America (25.4%) or Asian(20.7%). Patient accrual by geographic region, country and site was similar among the
3 treatment arms. The physical measurements at baseline were similar for the 3 treatment
arms. The median (range) values of Body Mass Index and body surface area (BSA) for theoverall population were 25.20 (range: 14.2 to 59.8) kg/m2 and 1.70 (range: 1.2 to 2.7) m2,
respectively.
The primary site of tumor was the ovary in the majority of patients (85.9%) followed by theperitoneum (8.7%) and the fallopian tube (5.5%). There were 251 (44.3%) patients who had
a platinum-free interval of 0 to 3 months and 248 (43.8%) patients who had a platinum-freeinterval of >3 to 6 months.

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Abbreviated Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS
Efficacy Results:
Primary – PFS Based on BICR Assessment
A Kaplan-Meier plot of PFS based on BICR is displayed in Figure 1. Median PFS based on
BICR assessment was 1.9 months (95% CI: 1.8, 1.9), 3.7 months (95% CI: 3.3, 5.1) and 3.5
months (95% CI: 2.1, 4.0) for the avelumab arm, the combination arm and the PLD arm,
respectively. PFS based on BICR assessment crossed the futility boundary for both
avelumab versus PLD and the combination treatment versus PLD comparisons at the time of
the interim analysis (IA). Updated results as of the data cutoff show a stratified hazard ratio
based on 279 PFS events of 1.68 (RCI: 1.320, 2.601; 1-sided nominal p-value: >0.9999) forcomparison between avelumab versus PLD, and a stratified hazard ratio based on 259 PFS
events of 0.78 (RCI: 0.587, 1.244; 1-sided nominal p-value: 0.0301) for comparison between
the combination treatment versus PLD.
Figure 1. Kaplan-Meier Plot of Progression-Free Survival (Primary Analysis) Basedon BICR Assessment (RECIST v1.1) – Full Analysis Set

Primary – OS
A Kaplan-Meier plot of OS is displayed in Figure 2. As of the data cutoff, median OS was
11.8 months (95% CI: 8.9, 14.1), 15.7 months (95% CI: 12.7, 18.7) and 13.1 months (95%
CI: 11.8, 15.5) for the avelumab arm, the combination arm and the PLD arm, respectively.
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OS crossed the futility boundary for the avelumab versus PLD comparison at the time of the
IA. Updated results show a stratified hazard ratio (avelumab versus PLD) of 1.14 (RCI:
0.948, 1.580; 1-sided nominal p-value: 0.8253) based on the 213 deaths. The stratified
hazard ratio (combination treatment versus PLD) based on 206 deaths was 0.89 (RCI: 0.744,
1.241; 1-sided p-value: 0.2082), in favor of the combination treatment. The observed p-value
for the combination treatment versus PLD did not cross the threshold for statisticalsignificance.
Figure 2. Kaplan-Meier Plot of Overall Survival - Full Analysis Set

Secondary - Sensitivity Analysis for PFS Based on BICR Assessment
The results of the sensitivity analyses were similar to those based on the primary analysis.
Secondary - Sensitivity Analysis for OS
The results of the sensitivity analyses were similar to those based on the primary analysis.
Secondary - PFS Based on Investigator Assessment
The outcome of the primary endpoint PFS based on BICR assessment was corroborated by
the outcome of the secondary endpoint, PFS based on investigator assessment. Consistent
with the BICR assessment, PFS based on investigator assessment was observed with astratified hazard ratio of 1.79 (95% CI: 1.403, 2.281; 1-sided p-value>0.9999) for thecomparison between avelumab versus PLD and 0.83 (95% CI: 0.648, 1.052, 1-sided
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p-value=0.0600) for the comparison between the combination treatment versus PLD(Figure 3).
Figure 3. Kaplan-Meier Plot of Progression-Free Survival Based on Investigator
Assessment (RECIST v1.1) - Full Analysis Set

Secondary - Best Overall Response (BOR)
The observed ORR based on BICR assessment was 3.7% (95% CI: 1.5, 7.5) for avelumab,
13.3% (95% CI: 8.8, 19.0) for the combination treatment, and 4.2% (95% CI: 1.8, 8.1) for
PLD. The stratified odds ratio was 0.890 (95% CI: 0.267, 2.901) and 3.458 (95% CI: 1.463,
9.096) for the comparison between avelumab and PLD and between the combination
treatment and PLD, respectively. The proportion of patients with a BOR of confirmed CR
was 0 for the avelumab and PLD arms, and 1.1% for the combination arm, whilst the
proportion of patients with a BOR of progressive disease was almost half in the combinationarm (31.9%) and the PLD arm (32.1%) as in the avelumab arm (53.7%).
The ORR based on investigator assessment was 5.3% (95% CI: 2.6, 9.6) for avelumab and9.5% (95% CI: 5.7, 14.6) for PLD, and 18.6% (95% CI: 13.3, 24.9) for the combination
treatment. The stratified odds ratio was 0.538 (95% CI: 0.216, 1.279) and 2.167 (95% CI:
1.145, 4.242) for the comparison between avelumab and PLD and the comparison between
the combination treatment and PLD, respectively.
Secondary - Time to Response and DR
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For patients who had an OR as assessed by BICR, the median time to response was
2.8 months for avelumab arm, 3.6 months for the combination arm and 3.7 months for the
PLD arm. The median DR as assessed by BICR for patients who responded was 9.2 months,
8.5 months and 13.1 months for the avelumab arm, the combination arm and the PLD arm,
respectively.
As assessed by the investigator, for patients who had an OR, the median time to response was
1.9 months for the avelumab arm, 3.7 months for the combination arm and 3.5 months for the
PLD arm.
Secondary - DCR
The DCR for the avelumab arm, the combination arm and the PLD arm was 33.0%, 57.4%
and 48.9%, respectively, based on the BICR assessment; and was 34.0%, 61.7% and 54.7%,
respectively, based on the investigator assessment.
Secondary - Patient-Reported Outcomes
The median TTD for EORTC QLQ-OV28 (the abdominal/GI subscale) was not estimable forthe avelumab arm, 11.1 months for the combination arm and 10.6 months for the PLD arm.
The hazard ratio (95% CI) was 1.41 (0.863, 2.306) for avelumab versus PLD and 1.24
(0.790, 1.934) for the combination treatment versus PLD.
Biomarker Results
Of the total population evaluable for the PD-L1 biomarker analysis, 57% had PD-L1 positive(PD-L1+) tumors; and the proportion of patients with PD-L1+ tumors of each treatment arm
was similar.
Within the combination arm, the median value of PFS based on BICR was slightly higher in
the PD-L1+ subgroup as compared to the PD-L1- subgroup. The unstratified hazard ratiowith respect to PFS based on BICR assessment in the PD-L1+ subgroup as compared to the
PD-L1 negative (PD-L1-) subgroup was 0.95 within the avelumab arm, 0.71 within the
combination arm and 1.16 within the PLD arm. The hazard ratios with respect to PFS in the
PD-L1- subgroup were greater than 1 for both the avelumab alone and combination arms
when compared to the PLD arm. The hazard ratios in the PD-L1+ subgroup were 1.45 foravelumab versus PLD and 0.65 for the combination treatment versus PLD.
Within the combination arm, the median value of OS was higher in the PD-L1+ subgroup ascompared to the PD-L1- subgroup. The unstratified hazard ratio with respect to OS in the
PD-L1+ subgroup as compared to the PD-L1- subgroup was 0.62 within the avelumab arm,
0.65 within the combination arm and 0.99 within the PLD arm. The hazard ratios withrespect to OS in the PD-L1- subgroup were greater than 1 for both the avelumab and the
combination arms when compared to the PLD arm. The hazard ratios in the PD-L1+
subgroup were 0.83 for the avelumab arm versus the PLD arm, and 0.72 for the combinationarm versus the PLD arm.
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Of the total population evaluable for the CD8 T cell biomarker analysis, 46% patients had
CD8+ tumors; and the proportion of patients with CD8+ tumors of each treatment arm was
similar.
Within the combination arm, the median value of PFS based on BICR was higher in the
CD8+ subgroup as compared to the CD8 negative (CD8-) subgroup. The unstratified hazard
ratio with respect to PFS based on BICR assessment in the CD8+ subgroup as compared to
the CD8- subgroup was 0.93 within the avelumab arm, 0.69 within the combination arm and0.95 within the PLD arm. Hazard ratios with respect to PFS in the CD8- subgroup were 1.53
and 0.92 for the avelumab arm and the combination arm respectively when compared to the
PLD arm. The hazard ratios in the CD8+ subgroup were 1.58 for the avelumab arm versus
the PLD arm, and 0.64 for the combination arm versus the PLD arm.
Within the combination arm, the median value of OS was higher in the CD8+ subgroup ascompared to the CD8- subgroup. The unstratified hazard ratio with respect to OS in the
CD8+ subgroup as compared to the CD8- subgroup was 0.89 within the avelumab arm, 0.62
within the combination arm and 0.88 within the PLD arm. Hazard ratios with respect to OS
in the CD8- subgroup were 1.01 and 0.97 for the avelumab arm and the combination arm
respectively when compared to the PLD. The hazard ratios in the CD8+ subgroup were 1.03
for the avelumab arm versus the PLD arm, and 0.66 for the combination arm versus the
combination arm.
Safety Results:
An overview of the treatment-emergent adverse events (TEAEs) is provided in Table 5. The
proportions of patients with TEAEs were similar among the treatment arms (96.3%, 98.8%
and 97.7% for avelumab, combination treatment and PLD, respectively). However the
combination treatment arm had a higher proportion of patients with treatment-related TEAEs,
grade 3 TEAEs or TEAEs leading to discontinuation from any study drug. The
treatment-emergent serious adverse event (SAE) incidence was higher in avelumab treatedpatients (avelumab alone [38.0%] and in combination [41.2%]), compared with the PLD arm(28.8%).

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Table 5.

MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Summary of Adverse Events During the On-Treatment
Period - Safety Analysis Set

Number (%) of Subjects
Subjects with TEAEs
Subjects with grade ≥ 3 TEAEs
Subjects with treatment-related TEAEs
Subjects with grade ≥ 3 treatment-related TEAEs
Subjects with serious TEAEs
Subjects with serious treatment-related TEAEs
Subjects with TEAEs leading to dose reduction of Avelumab
Subjects with TEAEs leading to dose reduction of PLD
Subjects with TEAEs leading to interruption of Avelumab
Subjects with TEAEs leading to interruption of PLD
Subjects with TEAEs leading to discontinuation of Avelumab
Subjects with TEAEs leading to discontinuation of PLD
Subjects with TEAEs leading to discontinuation of any study drug
Subjects with TEAEs leading to discontinuation of all study drugs
Subjects with treatment-related TEAEs leading to discontinuation of
AvelumabSubjects with treatment-related TEAEs leading to discontinuation of
PLD
Subjects with treatment-related TEAEs leading to discontinuation of
any study drug
Subjects with treatment-related TEAEs leading to discontinuation of all
study drugs
Subjects with TEAEs leading to death
Subjects with treatment-related TEAEs leading to death
Subjects with immune-related adverse events (irAEs)
Subjects with infusion-related reactions (IRRs)

Avelumab(N=187)n (%)

Avelumab + PLD(N=182)n (%)

PLD(N=177)n (%)

180 (96.3)
93 (49.7)
135 (72.2)
30 (16.0)
71 (38.0)
14 (7.5)0048 (25.7)
019 (10.2)
019 (10.2)
19 (10.2)
12 (6.4)

180 (98.9)
125 (68.7)
168 (92.3)
78 (42.9)
75 (41.2)
32 (17.6)
039 (21.4)
113 (62.1)
79 (43.4)
32 (17.6)
37 (20.3)
48 (26.4)
15 (8.2)
22 (12.1)

173 (97.7)
105 (59.3)
151 (85.3)
56 (31.6)
51 (28.8)
19 (10.7)
023 (13.0)057 (32.2)
0
18 (10.2)
18 (10.2)
18 (10.2)
0030 (16.5)

13 (7.3)

12 (6.4)

38 (20.9)

13 (7.3)

12 (6.4)8 (4.4)13 (7.3)

15 (8.0)
1 (0.5)25 (13.4)
38 (20.3)

8 (4.4)051 (28.0)30 (16.5)

6 (3.4)1 (0.6)8 (4.5)17 (9.6)

The denominator to calculate percentages is N, the number of subjects in the safety analysis set within each treatment group.
For combination arm, treatment-related AEs include AEs related to at least one study drug in the combination.
Any study drug = at least one study drug in the combination. All study drugs = all study drugs in the combination.
AEs leading to Interruption are AEs with action taken with study treatment of 'Drug interrupted' in CRF but excluding IRRs
that only lead to interruption of theinfusion.
MedDRA (v21.0) coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 30OCT2018 (17:50) Source Data: ADAE Output File:./B999_UNBLINDED/B9991009_CSR/adae_s020 Date of Generation: 26JAN2019 (08:53)
Table 14.3.1.2.1 is for Pfizer internal use.

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CLINICAL STUDY REPORT SYNOPSISThe TEAE incidences are summarized by Medical Dictionary for Regulatory Activities(MedDRA) preferred term (PT) and maximum Common Terminology Criteria for Adverse
Events (CTCAE) grade. The incidences of TEAEs with any grade in ≥10% and grade ≥3 in≥5% patients are presented in Table 6 (all-causality) and Table 7 (treatment-related).
More than half of the 533 patients with any TEAEs experienced TEAEs of grade 3(Table 6). Avelumab treated patients had higher incidences of Grade 5 TEAEs (8.0% and4.4% compared with 3.4% on PLD), most of which were coded as Disease progression PT.
The most frequent all-causality TEAEs in the combination arm (≥30% patients) were
Fatigue, Nausea, Anaemia and Palmar-plantar erythrodysaesthesia syndrome (Table 6). The
most frequent treatment-related TEAEs in the combination arm (≥30% patients) were
Fatigue, Nausea, and Palmar-plantar erythrodysaesthesia syndrome (Table 7).

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Table 6.

MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Summary of Most Common TEAEs (Any Grade in ≥10% Subjects or Grade ≥3 in ≥5% Subjects in Any Treatment Group), by
PT and Maximum CTCAE Grade During the On-Treatment Period - Safety
Analysis Set
Avelumab(N=187)

Avelumab + PLD(N=182)

PLD(N=177)

Preferred Term
All Grades(n %)Grade ≥ 3(n %)All Grades(n %)Grade ≥ 3 All Grades
(n %)
(n %)

Grade ≥ 3(n %)Subjects with events

180 (96.3)

93 (49.7)

180 (98.9)

125 (68.7)

173 (97.7)

105 (59.3)

Fatigue

63 (33.7)

4 (2.1)77 (42.3)

14 (7.7)

55 (31.1)

8 (4.5)

Abdominal pain

57 (30.5)

14 (7.5)

48 (26.4)

13 (7.1)

41 (23.2)

10 (5.6)

Nausea57 (30.5)

7 (3.7)89 (48.9)9 (4.9)77 (43.5)

2 (1.1)

Vomiting

47 (25.1)

7 (3.7)44 (24.2)

5 (2.7)45 (25.4)

4 (2.3)

Diarrhoea

43 (23.0)

9 (4.8)37 (20.3)

2 (1.1)32 (18.1)

4 (2.3)

Decreased appetite

38 (20.3)

4 (2.1)51 (28.0)

4 (2.2)37 (20.9)

1 (0.6)

Constipation

37 (19.8)

2 (1.1)

48 (26.4)

3 (1.6)45 (25.4)

1 (0.6)

Dyspnoea

36 (19.3)

8 (4.3)33 (18.1)

4 (2.2)25 (14.1)

2 (1.1)

Anaemia32 (17.1)

9 (4.8)55 (30.2)

12 (6.6)

42 (23.7)

16 (9.0)

Pyrexia32 (17.1)

1 (0.5)37 (20.3)

2 (1.1)17 (9.6)

1 (0.6)

Back pain

22 (11.8)

2 (1.1)17 (9.3)

3 (1.6)23 (13.0)

4 (2.3)Chills19 (10.2)

014 (7.7)

03 (1.7)0Asthenia

18 (9.6)

1 (0.5)30 (16.5)

8 (4.4)14 (7.9)

1 (0.6)Cough

17 (9.1)

028 (15.4)

024 (13.6)

0Abdominal distension

15 (8.0)

5 (2.7)18 (9.9)

1 (0.5)18 (10.2)

1 (0.6)

Headache15 (8.0)027 (14.8)

0

11 (6.2)

0Intestinal obstruction

15 (8.0)

15 (8.0)

13 (7.1)

8 (4.4)6 (3.4)6 (3.4)

Urinary tract infection

15 (8.0)

3 (1.6)20 (11.0)

1 (0.5)

14 (7.9)4 (2.3)

Infusion related reaction

13 (7.0)019 (10.4)

1 (0.5)16 (9.0)

1 (0.6)

Oedema peripheral

13 (7.0)

2 (1.1)25 (13.7)

1 (0.5)

14 (7.9)0Pruritus

13 (7.0)021 (11.5)

08 (4.5)0Rash

11 (5.9)051 (28.0)

11 (6.0)19 (10.7)

3 (1.7)

Hypothyroidism

8 (4.3)0

19 (10.4)

02 (1.1)0

Stomatitis

8 (4.3)1 (0.5)53 (29.1)

10 (5.5)

36 (20.3)

5 (2.8)Dry skin

5 (2.7)022 (12.1)

08 (4.5)1 (0.6)

Mucosal inflammation

4 (2.1)1 (0.5)25 (13.7)

3 (1.6)19 (10.7)

3 (1.7)

Neutropenia

1 (0.5)1 (0.5)26 (14.3)

10 (5.5)

26 (14.7)

9 (5.1)PFIZER CONFIDENTIAL
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CLINICAL STUDY REPORT SYNOPSIS
Table 6.

MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Summary of Most Common TEAEs (Any Grade in ≥10% Subjects or Grade ≥3 in ≥5% Subjects in Any Treatment Group), by
PT and Maximum CTCAE Grade During the On-Treatment Period - Safety
Analysis Set
Avelumab(N=187)

Avelumab + PLD(N=182)

PLD(N=177)

Preferred Term

Palmar-plantar erythrodysaesthesia
syndrome

All Grades(n %)Grade ≥ 3(n %)All Grades(n %)Grade ≥ 3 All Grades
(n %)
(n %)

1 (0.5)061 (33.5)

18 (9.9)40 (22.6)

Grade ≥ 3(n %)
9 (5.1)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 (v21.0) coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 30OCT2018 (17:50) Source Data: ADAE Output File:./B999_UNBLINDED/B9991009_CSR/adae_s999a Date of Generation: 26JAN2019 (09:00)
Table 14.3.1.2.6 is for Pfizer internal use.

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Table 7.

MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Summary of Most Common Treatment-related TEAEs(Any Grade in ≥10% Subjects or Grade ≥3 in ≥5% Subjects in Any
Treatment Group), by PT and Maximum CTCAE Grade During the OnTreatment Period - Safety Analysis Set
Avelumab(N=187)

Avelumab + PLD(N=182)

PLD(N=177)

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

135 (72.2)

30 (16.0)

168 (92.3)

78 (42.9)

151 (85.3)

56 (31.6)

Fatigue
NauseaDiarrhoea
Pyrexia
Anaemia
Vomiting
Infusion related reaction
Decreased appetite
Rash
Asthenia
Pruritus
Mucosal inflammation
Stomatitis
Palmar-plantar erythrodysaesthesia
syndrome
Neutropenia

42 (22.5)
25 (13.4)
24 (12.8)
21 (11.2)
19 (10.2)
16 (8.6)
13 (7.0)
11 (5.9)9 (4.8)8 (4.3)7 (3.7)4 (2.1)4 (2.1)1 (0.5)00
5 (2.7)0
3 (1.6)
1 (0.5)00
000
1 (0.5)0060 (33.0)
65 (35.7)
19 (10.4)
22 (12.1)
39 (21.4)
21 (11.5)
19 (10.4)
33 (18.1)
45 (24.7)
21 (11.5)
19 (10.4)
24 (13.2)
51 (28.0)
60 (33.0)

10 (5.5)
3 (1.6)
1 (0.5)0
6 (3.3)1 (0.5)1 (0.5)1 (0.5)
11 (6.0)
4 (2.2)0
3 (1.6)
10 (5.5)
18 (9.9)42 (23.7)
64 (36.2)
20 (11.3)
5 (2.8)34 (19.2)
28 (15.8)
14 (7.9)26 (14.7)
16 (9.0)
9 (5.1)6 (3.4)17 (9.6)
36 (20.3)
40 (22.6)

3 (1.7)1 (0.6)00
9 (5.1)3 (1.7)1 (0.6)0
3 (1.7)1 (0.6)0
3 (1.7)5 (2.8)9 (5.1)00

24 (13.2)

9 (4.9)26 (14.7)

9 (5.1)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.
For combination arm, treatment-related AEs include AEs related to at least one study drug in the combination.
MedDRA (v21.0) coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 30OCT2018 (17:50) Source Data: ADAE Output File:./B999_UNBLINDED/B9991009_CSR/adae_s999b Date of Generation: 26JAN2019 (09:38)
Table 14.3.1.3.1.1 is for Pfizer internal use.

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Abbreviated Clinical Study Report
Protocol B9991009

CLINICAL STUDY REPORT SYNOPSIS
A summary for all-grade and grade 3 immune-related AE (irAE) incidences are presented inTable 8. As expected based on avelumab’s mechanism of action, the proportion of patientswith irAEs was higher in the avelumab arm and in the combination arm than in the PLD arm(13.4% and 28.0% versus 4.5% for all grades, 3.7% and 8.2% versus 0.6% for grade 3).
The most common irAE categories were “Immune-related Endocrinopathies: Thyroid
Disorders” (5.9%, 9.9% and 1.1% in the avelumab arm, the combination arm and the PLDarm, respectively) and “Immune-related Rash” (3.2%, 18.1% and 3.4% in the avelumab arm,the combination arm and the PLD arm, respectively).

Table 8.

MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Summary of irAEs by Cluster, PT and Maximum
CTCAE Grade - Safety Analysis Set
Avelumab(N=187)All
Grade≥3
Gradesn (%)
n (%)

Avelumab + PLD(N=182)All
Grade≥3
Grades
n (%)
n (%)

PLD
(N=177)All
Grade≥3
Gradesn (%)
n (%)

Subjects with events

25 (13.4)

7 (3.7)51 (28.0)

15 (8.2)

8 (4.5)1 (0.6)IMMUNE-RELATED ENDOCRINOPATHIES:
THYROID DISORDERS
Hypothyroidism
Hyperthyroidism
Autoimmune thyroiditis
Basedow's disease
IMMUNE-RELATED RASH
Rash
Rash erythematous
Rash macular
Rash maculo-papular
Dermatitis exfoliative generalised
Drug eruption
ErythemaPruritus
Rash papular
Rash pruritic
Skin toxicity
Toxic skin eruption
IMMUNE-RELATED HEPATITIS
Alanine aminotransferase increased
Aspartate aminotransferase increased

11 (5.9)

1 (0.5)18 (9.9)02 (1.1)0

7 (3.7)5 (2.7)00
6 (3.2)4 (2.1)1 (0.5)1 (0.5)1 (0.5)
0
0
0
0
0
0
0
0
4 (2.1)2 (1.1)2 (1.1)0
1 (0.5)00
1 (0.5)0
1 (0.5)
0
0
0
0
0
0
0
0
0
0
3 (1.6)
1 (0.5)2 (1.1)17 (9.3)
3 (1.6)
1 (0.5)1 (0.5)33 (18.1)
20 (11.0)
1 (0.5)1 (0.5)7 (3.8)0
1 (0.5)1 (0.5)4 (2.2)1 (0.5)2 (1.1)2 (1.1)1 (0.5)1 (0.5)1 (0.5)00
0
00
12 (6.6)
7 (3.8)00
4 (2.2)00
000
1 (0.5)00
1 (0.5)1 (0.5)02 (1.1)000
6 (3.4)2 (1.1)0
1 (0.6)
1 (0.6)
1 (0.6)00
0
0
1 (0.6)
0
0
0
0
0

0
0
0
0
1 (0.6)00
0
0
1 (0.6)
0
0
0
0
0
0
0
0
0
0

Clusterand Preferred Term

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Protocol B9991009

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Table 8.

MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Summary of irAEs by Cluster, PT and Maximum
CTCAE Grade - Safety Analysis Set

Clusterand Preferred Term
Autoimmune hepatitis
Drug-induced liver injury
Hepatitis
IMMUNE-RELATED PNEUMONITIS
Pneumonitis
OTHER IMMUNE-RELATED ADVERSEEVENTS
Rheumatoid arthritis
Sjogren's syndrome
IMMUNE-RELATED COLITIS
Diarrhoea
ColitisIMMUNE-RELATED ENDOCRINOPATHIES:
ADRENAL INSUFFICIENCY
Adrenal insufficiency
IMMUNE-RELATED ENDOCRINOPATHIES:PITUITARY DYSFUNCTION
Hypopituitarism

Avelumab(N=187)All
Grade≥3
Gradesn (%)
n (%)

Avelumab + PLD(N=182)All
Grade≥3
Grades
n (%)
n (%)

PLD
(N=177)All
Grade≥3
Gradesn (%)
n (%)

1 (0.5)1 (0.5)1 (0.5)4 (2.1)4 (2.1)2 (1.1)1 (0.5)1 (0.5)0
1 (0.5)1 (0.5)0000
3 (1.6)3 (1.6)
0

0
0
0
0
0
0

0
0
0
0
0
0

0
0
0
0
0
0

1 (0.5)1 (0.5)1 (0.5)1 (0.5)0000
1 (0.5)1 (0.5)0000
1 (0.5)0
1 (0.5)2 (1.1)00
1 (0.5)0
1 (0.5)1 (0.5)

0
0
0
0
0
0

0
0
0
0
0
0

0
0

0
0

2 (1.1)2 (1.1)1 (0.5)1 (0.5)

0
0

0
0

0

0

2 (1.1)1 (0.5)00

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.
Subjects reporting multiple preferred terms within the same cluster are counted only once within each cluster.
For subjects reporting more than one AE within a cluster or preferred term, the AE with maximum grade is included in thetable.
MedDRA (v21.0) coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 30OCT2018 (17:50) Source Data: ADAEI Output File:./B999_UNBLINDED/B9991009_CSR/adae_s062_irae3 Date of Generation: 26JAN2019 (09:44)
Table 14.3.3.3.1.1.1.1 is for Pfizer internal use.

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CLINICAL STUDY REPORT SYNOPSIS
A summary for infusion-related reactions (IRR) incidences are presented in Table 9. There
were 38 (20.3%), 30 (16.5%) and 17 (9.6%) patients that experienced a TEAE that met thecase definition of an IRR in the avelumab, combination and PLD arms, respectively. The
most commonly reported IRR PT was Infusion related reaction, experienced by 13 (7.0%)
patients in the avelumab arm, 11 (6.0%) patients in the combination arm and 14 (7.9%)
patients in the PLD arm.

Table 9.

MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Summary of IRRs - Safety Analysis Set
Avelumab(N=187)n (%)

Avelumab + PLD(N=182)n (%)

PLD(N=177)n (%)

Subjects with IRR
ChillsInfusion related reaction
Pyrexia
Abdominal pain
Drug hypersensitivity
Flushing
Hypersensitivity
Hypotension
Anaphylactic reaction
Back pain
Dyspnoea
Urticaria
Wheezing

38 (20.3)
13 (7.0)
13 (7.0)
12 (6.4)
1 (0.5)1 (0.5)1 (0.5)1 (0.5)1 (0.5)0000030 (16.5)
11 (6.0)
11 (6.0)
10 (5.5)
01 (0.5)0
1 (0.5)00
1 (0.5)000

17 (9.6)
0
14 (7.9)
1 (0.6)
1 (0.6)0
2 (1.1)1 (0.6)0
1 (0.6)0
1 (0.6)2 (1.1)1 (0.6)

Subjects with IRR (maximum severity)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Grade ≥ 3

24 (12.8)
14 (7.5)0000

14 (7.7)
15 (8.2)
1 (0.5)00
1 (0.5)3 (1.7)
12 (6.8)
1 (0.6)
1 (0.6)0
2 (1.1)

Subjects with IRR leading to discontinuation

2 (1.1)1 (0.5)2 (1.1)

Subjects with serious IRR

5 (2.7)6 (3.3)2 (1.1)PFIZER CONFIDENTIAL
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Table 9.

MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Summary of IRRs - Safety Analysis Set
Avelumab(N=187)n (%)

Avelumab + PLD(N=182)n (%)

PLD(N=177)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 within a preferred term are counted only once in that preferred term.
MedDRA (v21.0) coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 30OCT2018 (17:50) Source Data: ADAE Output File:./B999_UNBLINDED/B9991009_CSR/adae_irr_s Date of Generation: 26JAN2019 (10:01)
Table 14.3.3.3.2.1.3 is for Pfizer internal use.

There was a higher proportion of patients in the combination arm with TEAEs leading topermanent discontinuation of either study drug compared with avelumab and PLD (26.4%
versus 10.2% and 10.2%, respectively). The proportion of patients who discontinued bothstudy drugs was similar across treatment arms (8.2% versus 10.2% and 10.2% patients,
respectively). The most common TEAE leading to the discontinuation of avelumab was
Intestinal obstruction (1.6% and 0.5% patients on avelumab and on the combination
treatment, respectively). The most common TEAE leading to the discontinuation of PLD
was Palmar-plantar erythrodysaesthesia syndrome (4.4% and 1.7% patients in the
combination treatment and PLD arms, respectively).

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Abbreviated Clinical Study Report
Protocol B9991009

CLINICAL STUDY REPORT SYNOPSIS
As of the data cutoff, 57.8% patients in the avelumab arm, 53.8% patients in the combination
arm, and 58.2% patients in the PLD arm had died. The primary reason for death was diseaseprogression (48.7% patients in the avelumab arm, 50.5% patients in the combination arm and50.8 % patients in the PLD arm). TEAEs leading to death are summarized by system organclass (SOC) and PT in Table 10.

Table 10. MSB0010718C Protocol B9991009 - (Cutoff date: 19SEP2018, Snapshot
Date: 29OCT2018) Summary of TEAEs During the On-Treatment Period
Leading to Death by SOC and PT - Safety Analysis Set
Avelumab(N=187)n (%)

Avelumab + PLD(N=182)n (%)

PLD(N=177)n (%)

Subjects with events

15 (8.0)

8 (4.4)6 (3.4)General disorders and administration site conditions
Disease progression
General physical health deterioration
Gastrointestinal disorders
Intestinal obstruction
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration
Lung disorder
Pulmonary embolism
Infections and infestations
Meningitis
SepsisNeoplasms benign, malignant and unspecified (incl cysts andpolyps)Malignant neoplasm progression

11 (5.9)9 (4.8)2 (1.1)3 (1.6)3 (1.6)
1 (0.5)1 (0.5)
0
0
0
0
0
0

6 (3.3)5 (2.7)1 (0.5)00
0
0
00
1 (0.5)1 (0.5)0
1 (0.5)2 (1.1)2 (1.1)0
1 (0.6)
1 (0.6)2 (1.1)0
1 (0.6)
1 (0.6)
1 (0.6)0
1 (0.6)00

1 (0.5)0

System Organ Classand 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 within a preferred term are counted only once in that preferred term.
Subjects reporting multiple preferred terms within the same system organ class (SOC) are counted only once within each
SOC.
MedDRA (v21.0) coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 30OCT2018 (17:50) Source Data: ADAE Output File:./B999_UNBLINDED/B9991009_CSR/adae_s050 Date of Generation: 26JAN2019 (08:55)
Table 14.3.1.2.4 is for Pfizer internal use.

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Abbreviated Clinical Study Report
Protocol B9991009

CLINICAL STUDY REPORT SYNOPSIS
The most common serious TEAEs were Intestinal obstruction and Abdominal pain. The
most common treatment-related serious TEAE was Pyrexia, reported in the avelumab arm
and in the combination arm.
Overall, there was a higher proportion of liver function test (LFT) abnormalities in the
combination arm. None of the abnormalities met the criteria for a potential Hy’s Law case.
The proportions of patients with the QT interval corrected using Fridericia’s Formula (QTcF)>500 msec or QTcF changes from baseline >60 msec were small and similar among the
3 treatment arms. One [1 (0.8%)], 1 (0.6%) and 2 (1.5%) patients, respectively, had a Left
Ventricular Ejection Fraction (LVEF)% ≥15 points decrease from baseline to a post baseline
value <lower limit of normal (LLN); and 1 (0.8%), 3 (1.9%), and 2 (1.5%) patients,
respectively, had a LVEF% ≥10 points decrease from baseline to a post baseline value <LLN.
Conclusions:

Avelumab, administered alone or in combination with PLD, was not superior to PLD
monotherapy in prolonging PFS (as assessed by BICR) or OS, in the treatment of patientswith platinum resistant/refractory ovarian cancer.

The observed ORR based on BICR assessment was higher for avelumab administered in
combination with PLD and similar for avelumab alone compared with that for PLD alone.



The results of the analyses for tumor-related efficacy endpoints based on investigatorassessment were similar to those based on BICR assessment.



PFS and OS were extended following treatment with avelumab in combination with PLD
compared to PLD alone in patients whose tumors expressed PD-L1 and in thosecontaining CD8+ T-cells, when compared to patients whose tumors did not express thesemarkers. These data, while not conclusive in the context of this study, indicate that
PD-L1 expression or the presence of CD8 T-cells have potential as predictive biomarkers
for the activity of avelumab in combination with PLD in this patient population.

The observed TTD results, as measured by the abdominal/GI subscale of the EORTCQLQ-OV28 were similar for avelumab, either alone or in combination, compare to PLD
alone.

The safety profile of avelumab, administered alone or in combination with PLD, wasgenerally tolerable, manageable, and consistent with the known safety profiles ofavelumab and PLD when administered as monotherapies.

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