Final Clinical Study Report
Protocol JAVELIN OVARIAN 100 (B9991010)

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc.
Investigational Product: Avelumab, Compound Number: PF-06834635
Clinical Study Report Synopsis: Protocol JAVELIN OVARIAN 100 (B9991010)
Protocol Title: A Randomized, Open-Label, Multicenter, Phase 3 Study to Evaluate theEfficacy and Safety of Avelumab (MSB0010718C) in Combination With and/or Following
Chemotherapy in Patients With Previously Untreated Epithelial Ovarian Cancer
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: 19 May 2016.
Report Date: 05 September 2019
Previous Report Date(s): Not applicable.
Phase of Development: Phase 3

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Final Clinical Study Report
Protocol JAVELIN OVARIAN 100 (B9991010)

CLINICAL STUDY REPORT SYNOPSIS
Primary and Secondary Study Objectives and Endpoints:
Table S1. Study Objectives and Endpoints
Type
Primary
Efficacy

Secondary
Efficacy

Objective

Endpoint

To demonstrate that avelumab in combination with platinum-based
chemotherapy followed by avelumab maintenance is superior toplatinum-based chemotherapy alone followed by observation in
prolonging progression-free survival (PFS) in patients withpreviously untreated epithelial ovarian cancer (EOC).
To demonstrate that platinum-based chemotherapy alone followedby avelumab maintenance is superior to platinum-based
chemotherapy alone followed by observation in prolonging PFS inpatients with previously untreated EOC.

PFS as determined by blinded independent central review (BICR) by
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

To compare avelumab in combination with platinum-based
chemotherapy followed by avelumab maintenance andplatinum-based chemotherapy alone followed by avelumab
maintenance to platinum-based chemotherapy alone followed byobservation in patients with previously untreated EOC, with respect
to overall survival (OS).
To evaluate the anti-tumor activity in each treatment arm.

OS

SafetyTo evaluate the overall safety profile in each treatment arm.

PK
(None Reported)

To evaluate the pharmacokinetics (PK) of paclitaxel and carboplatinalone and in combination with avelumab.

To evaluate the PK of avelumab alone and in combination withPFS as determined by BICR by RECIST v1.1

PFS by Investigator assessment
Objective response (OR); Duration of response (DR); Maintenance
PFS (mPFS) by BICR assessment and Investigator assessment;
pathologic complete response (pCR); PFS2; and PFS by
Gynecological Cancer Intergroup (GCIG) criteria.
Adverse events (AEs) (as graded by National Cancer Institute [NCI]
Common Terminology Criteria for Adverse Events [CTCAE] v4.03);
laboratory abnormalities (as graded by NCI CTCAE v4.03); vital
signs (blood pressure, pulse rate); electrocardiograms (ECGs)
PK Parameters, including Minimum (trough) observed drugconcentration (Ctrough), maximum concentration (Cmax), volume of
distribution, (Vd), clearance (CL), area under the concentration time
curve (AUC) for avelumab, paclitaxel, and carboplatin, as data
permit.
PK Parameters, including Ctrough, Cmax, Vd, CL, AUC for avelumab,

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Protocol JAVELIN OVARIAN 100 (B9991010)

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints
Type
Immunogenicity(None Reported)

PRO(None Reported)

Objective
carboplatin-paclitaxel.
To evaluate the immunogenicity of avelumab alone and incombination with carboplatin-paclitaxel.

Endpoint
paclitaxel, and carboplatin, as data permit.
Anti-drug antibodies (ADA) and neutralizing antibody (nAb) against
avelumab.

To evaluate patient-reported outcome (PRO) in the experimental
arms versus the control arm in patients with previously untreated
EOC including the assessment of treatment side effects anddisease-related symptoms.

Functional Assessment of Cancer Therapy Ovarian Symptom Index
18 (FOSI-18) and EuroQoL5 Dimension (EQ-5D-5L)

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Protocol JAVELIN OVARIAN 100 (B9991010)

CLINICAL STUDY REPORT SYNOPSISMETHODS
Study Design: This was a Phase 3, open-label, international, multi-center, efficacy, andsafety study of avelumab in combination with and/or following platinum-based
chemotherapy.
In this Phase 3 trial, approximately 951 patients who were candidates for frontline
platinum-based chemotherapy were to be randomized in a 1:1:1 ratio stratified by paclitaxel
regimen (once every 3 weeks [Q3W] versus once weekly [QW]) and by adjuvant (complete
resection/microscopic disease) versus adjuvant (incomplete resection ≤1 cm) versus adjuvant(incomplete resection 1 cm) versus neoadjuvant to one of the following treatment arms.
Treatment Arms:

Arm A: platinum-based chemotherapy alone followed by observation (control arm)

Arm B: platinum-based chemotherapy alone followed by avelumab maintenance(experimental arm)

Arm C: platinum-based chemotherapy in combination with avelumab followed by
avelumab maintenance (experimental arm)

Diagnosis and Main Criteria for Inclusion: Patients with previously untreated, Stage III-IV
epithelial ovarian cancer (EOC), Fallopian tube cancer (FTC), or primary peritoneal cancer(PPC) who were candidates for platinum-based chemotherapy.
Study Treatment: All patients received chemotherapy consisting of carboplatin
administered Q3W in combination with paclitaxel either QW or Q3W. Patients in one of theexperimental arms also received avelumab Q3W in combination with thecarboplatin/paclitaxel regimen. Patients in both experimental arms received avelumab every
2 weeks (Q2W) during the maintenance phase (after completion of the chemotherapy
regimen). Patients received carboplatin, paclitaxel, and avelumab as intravenous (IV)infusions. Avelumab investigational product description is presented in Table S2 (seeAppendix 16.1.6 for complete list of investigational product descriptions).

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Final Clinical Study Report
Protocol JAVELIN OVARIAN 100 (B9991010)

CLINICAL STUDY REPORT SYNOPSIS
Table S2. Avelumab 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)
Source: Appendix 16.1.6.

Vendor Lot
No.

Pfizer Lot No.

Strength/Potency

Dosage Form

PD1F004

15-006068

200 mg

SOLUTION

PD1F01316-000916

200 mg

SOLUTION

PD1G003

16-003176

200 mg

SOLUTION

PD1E002

15-002315

200 mg

SOLUTION

Efficacy Endpoints:
Primary Efficacy Endpoint: Progression-free survival (PFS) as determined by blinded
independent central review (BICR) by Response Evaluation Criteria in Solid Tumors(RECIST) v1.1. PFS is defined as the time from the date of randomization to the date of thefirst documentation of progressive disease (PD) based on BICR assessment or death due toany cause, whichever occurs first.
Secondary Efficacy Endpoints:
Overall survival (OS) is defined as the time from the date of randomization to the date ofdeath due to any cause. PFS is defined as the time from the date of randomization to the dateof the first documentation of PD based on investigator assessment or death due to any cause,
whichever occurs first. Other secondary efficacy endpoints included objective response(OR), duration of response (DR), maintenance PFS by BICR assessment, and pathologic
complete response (pCR).
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.
Statistical Methods:
The study was designed to test, in parallel, 2 hypotheses:

The true PFS hazard ratio (HR) for chemotherapy in combination with avelumab
followed by avelumab maintenance over chemotherapy alone followed by observation
was ≥1; versus the alternative hypothesis that the true HR was 1.



The true PFS HR for chemotherapy alone followed by avelumab maintenance overchemotherapy alone followed by observation was ≥1; versus the alternative hypothesisthat the true HR was 1.

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Protocol JAVELIN OVARIAN 100 (B9991010)

CLINICAL STUDY REPORT SYNOPSISRESULTS
Patient Disposition and Demography:
A summary of patient disposition at the end of treatment chemotherapy phase is presented inTable S3. Within each treatment arm the majority of patients completed the chemotherapy
phase. Patients discontinued from the study during the chemotherapy phase most often due
to AEs, withdrawal by subject, and PD.
A summary of patient disposition at the end of treatment maintenance phase is presented inTable S4. Within each treatment arm approximately half of the patients were ongoing at thetime of data cut off. Patients discontinued from the study during the maintenance phase mostoften due to withdrawal by subject and PD.
Overall, demographic characteristics were balanced across treatment arms. All enrolled
patients were female, most were <65 years old, and the majority were white.

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Final Clinical Study Report
Protocol JAVELIN OVARIAN 100 (B9991010)

CLINICAL STUDY REPORT SYNOPSIS
Table S3. Subject Disposition for Study Drugs at End of Treatment Chemotherapy Phase - Full Analysis Set
Chemotherapy -> Avelumab(N=332)

Chemotherapy + Avelumab -> Avelumab(N=331)

Chemotherapy -> Observation(N=335)

Paclitaxel

Carboplatin

AvelumabPaclitaxel

Carboplatin

Paclitaxel

Carboplatin

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

57 (17.2)

52 (15.7)

47 (14.2)

50 (15.1)

41 (12.4)

56 (16.7)

45 (13.4)

Death

5 (1.5)5 (1.5)4 (1.2)4 (1.2)4 (1.2)1 (0.3)1 (0.3)

Progressive disease

11 (3.3)

11 (3.3)

7 (2.1)7 (2.1)7 (2.1)

10 (3.0)

10 (3.0)

Adverse event

14 (4.2)

8 (2.4)23 (6.9)

26 (7.9)

17 (5.1)

24 (7.2)

13 (3.9)

Physician’s decision

5 (1.5)6 (1.8)3 (0.9)1 (0.3)1 (0.3)4 (1.2)4 (1.2)

No longer meets eligibility criteria

4 (1.2)4 (1.2)2 (0.6)2 (0.6)2 (0.6)

1 (0.3)1 (0.3)

Disposition phase: end of chemotherapy
Discontinued
Reason for discontinuation

Global deterioration of health status

4 (1.2)3 (0.9)2 (0.6)2 (0.6)2 (0.6)

1 (0.3)1 (0.3)

Withdrawal by subject

12 (3.6)

13 (3.9)

6 (1.8)8 (2.4)8 (2.4)15 (4.5)

15 (4.5)

2 (0.6)2 (0.6)

0

0

0

0

0

Completed

Other

275 (82.8)

280 (84.3)

284 (85.8)

281 (84.9)

290 (87.6)

279 (83.3)

290 (86.6)

Ongoing

0

0

0

0

0

0

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: 14MAY2019 (23:39) Source Data: ADDS Output File: ./B9991010_restricted/B9991010_CSR/adds_s001g Date of Generation:
06JUN2019 (15:54)
Table 14.1.1.2.7 is for Pfizer internal use.

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Final Clinical Study Report
Protocol JAVELIN OVARIAN 100 (B9991010)

CLINICAL STUDY REPORT SYNOPSIS
Table S4. Subject Disposition for Study Drugs at End of Treatment Maintenance Phase - Full Analysis Set
Chemotherapy -> Avelumab(N=332)

Chemotherapy + Avelumab -> Avelumab(N=331)

Chemotherapy -> Observation(N=335)

AvelumabAvelumabObservation

n (%)

n (%)

n (%)

112 (33.7)

107 (32.3)

114 (34.0)01 (0.3)2 (0.6)

Progressive disease72 (21.7)

64 (19.3)

66 (19.7)

Adverse event

16 (4.8)

23 (6.9)

1 (0.3)

Physician’s decision

4 (1.2)5 (1.5)9 (2.7)

Protocol deviation

0

0

0

Study terminated by sponsor

00

1 (0.3)

No longer meets eligibility criteria01 (0.3)0

Disposition phase: end of maintenanceDiscontinued
Reason for discontinuation
Death

Global deterioration of health status

5 (1.5)2 (0.6)

1 (0.3)

Withdrawal by subject

13 (3.9)

10 (3.0)27 (8.1)00

2 (0.6)2 (0.6)

1 (0.3)5 (1.5)

Lost to follow-up
Other
Completed00

1 (0.3)

Ongoing

155 (46.7)

180 (54.4)

172 (51.3)

The denominator to calculate percentages is N, the number of subjects in the full analysis set within each treatment group.
PFIZER CONFIDENTIAL SDTM Creation: 14MAY2019 (23:39) Source Data: ADDS Output File: ./B9991010_restricted/B9991010_CSR/adds_s001h Date of Generation:
06JUN2019 (16:00)
Table 14.1.1.2.8 is for Pfizer internal use.

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Protocol JAVELIN OVARIAN 100 (B9991010)

CLINICAL STUDY REPORT SYNOPSIS
Primary Efficacy Results:
The study did not meet its primary endpoint of PFS as assessed by BICR in either
experimental arm. The stratified HRs comparing each of the experimental arms against thecontrol arm were 1 favoring the control arm: 1.43, 95% confidence interval (CI) (1.051,
1.946) for chemotherapy alone followed by avelumab maintenance and 1.14, 95% CI (0.832,
1.565) for chemotherapy in combination with avelumab followed by avelumab maintenance(Figure S1).
Figure S1. Kaplan-Meier Plot of Progression-Free Survival (Primary Analysis) Basedon BICR Assessment (RECIST v1.1) - Full Analysis Set

Abbreviations: BICR = blinded independent central review; CI = confidence interval; HR = hazard ratio;
NE = not evaluable; RECIST = Response Evaluation Criteria in Solid Tumors.

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Protocol JAVELIN OVARIAN 100 (B9991010)
Secondary Efficacy Results:
The OS data were still immature at the time of the analysis. The stratified HRs in bothexperimental arms compared to the control arm were 1, favoring the control arm.
Despite a higher early discrepancy rate (reflecting a higher frequency with which investigator
declared PFS events earlier than BICR), the results for PFS based on investigator assessment
were similar to those observed based on BICR assessment.
The Objective Response Rate was similar across the treatment arms based on both BICR
(30.4% for patients who received chemotherapy alone followed by observation, 30.4% forpatients who received chemotherapy alone followed by avelumab maintenance, 36.0% forpatients who received chemotherapy in combination with avelumab followed by avelumab
maintenance) and investigator assessment (27.8% for patients who received chemotherapy
alone followed by observation, 25.9% for patients who received chemotherapy alone
followed by avelumab maintenance, 31.1% for patients who received chemotherapy in
combination with avelumab followed by avelumab maintenance).
The median DR was not reached in any of the treatment arms.
Maintenance PFS time (based on BICR and based on investigator assessment) appeared to be
similar across treatment arms; median maintenance PFS was not reached in any of thetreatment arms.
The observed pCR rates for patients in the experimental arms (15.7% for patients who
received chemotherapy alone followed by avelumab maintenance, 17.4% for patients who
received chemotherapy in combination with avelumab followed by avelumab maintenance)
were lower than that observed for patients in the control arm (25.9%).
Safety Results:
The overall proportions of patients who reported treatment-emergent adverse events (TEAEs)
were similar across treatment arms. In general, the control arm had the lowest and thetreatment arm of chemotherapy in combination with avelumab followed by avelumab
maintenance had the highest proportions of patients with TEAEs of all causality, treatmentrelated TEAEs of Grade ≥3, serious TEAEs, TEAEs leading to interruption or
discontinuation of any study drug, and infusion-related adverse events (irAEs). Higher
proportions of patients in the experimental arms experienced serious TEAEs or serious
treatment-related TEAEs compared to patients in the control arm. Deaths occurred more
frequently in the experimental arms than in the control arm, and were most often due todisease progression.
Deaths occurred in 19 patients (5.8%) who received chemotherapy alone followed by
avelumab maintenance and 21 patients (6.4%) who received chemotherapy with avelumab
followed by avelumab maintenance compared with 13 patients (3.9%) who received
chemotherapy alone followed by observation. These deaths were most often due to diseaseprogression (15 patients [4.6%] who received chemotherapy alone followed by avelumab
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Final Clinical Study Report
Protocol JAVELIN OVARIAN 100 (B9991010)
maintenance, 17 patients [5.2%] who received chemotherapy with avelumab followed by
avelumab maintenance, and 11 patients [3.3%] who received chemotherapy alone followed
by observation).
TEAEs during the on-treatment period leading to death occurred in 2% of patients in alltreatment arms. Treatment-related TEAEs during the on-treatment period leading to death
only occurred in 1 patient who received chemotherapy alone followed by avelumab
maintenance (preferred term [PT] of atrial fibrillation; of note, this AE had an onset during
the chemotherapy phase prior to initiating avelumab) and 1 patient who received
chemotherapy with avelumab followed by avelumab maintenance (PT of diseaseprogression). No patient had an irAE or immune-related reaction (IRR) leading to death.
TEAEs leading to permanent discontinuation of any study drug was reported for 11.3% of
patients who received chemotherapy alone followed by avelumab maintenance, 19.1% of
patients who received chemotherapy with avelumab followed by avelumab maintenance, and7.5% of patients who received chemotherapy alone followed by observation.
Treatment-related TEAEs leading to permanent discontinuation of any study drug wasreported for 9.8% of patients who received chemotherapy alone followed by avelumab
maintenance, 15.5% of patients who received chemotherapy with avelumab followed by
avelumab maintenance, and 6.6% of patients who received chemotherapy alone followed byobservation.
Discontinuations of any study drug due to irAEs occurred in 8 patients (2.4%) who received
chemotherapy alone followed by avelumab maintenance and 19 patients (5.8%) who received
chemotherapy with avelumab followed by avelumab maintenance. Discontinuations of any
study drug due to IRRs occurred in 3 patients (0.9%) who received chemotherapy alone
followed by avelumab maintenance and 7 patients (2.1%) who received chemotherapy withavelumab followed by avelumab maintenance compared with 4 patients (1.2%) who received
chemotherapy alone followed by observation.
The proportions of patients who reported TEAEs were similar across treatment arms
(Table S5). The most frequent all-causality TEAEs (all grades) experienced by ≥30% of
patients in all 3 treatment arms were alopecia, anemia, nausea, neutropenia, and fatigue.
Constipation was also reported by ≥30% of patients who received chemotherapy alone
followed by avelumab maintenance. Serious treatment-related TEAEs were experienced by
42 patients (12.8%) who received chemotherapy alone followed by avelumab maintenance,
63 patients (19.1%) who received chemotherapy with avelumab followed by avelumab
maintenance, and 29 patients (8.7%) who received chemotherapy alone followed byobservation. Patients who received chemotherapy with avelumab followed by avelumab
maintenance had the highest proportions of patients with serious treatment-related TEAEs.
The most common serious TEAEs (any grade in ≥2% of patients or Grade ≥3 in ≥2% of
patients) were pyrexia, anaemia, febrile neutropenia, urinary tract infection and ileus in all
3 treatment arms and in general were experienced by higher proportions of patients who
received chemotherapy with avelumab followed by avelumab maintenance followed bypatients who received chemotherapy alone followed by avelumab maintenance compared topatients who received chemotherapy alone followed by observation (Table S6).
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Final Clinical Study Report
Protocol JAVELIN OVARIAN 100 (B9991010)
Table S5. 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
Chemotherapy ->Avelumab(N=328)Chemotherapy +Avelumab -> Avelumab(N=329)Chemotherapy ->Observation(N=334)Preferred Term
All Grades(n %)Grade ≥ 3(n %)All Grades(n %)Grade ≥ 3(n %)All Grades(n %)Grade ≥ 3(n %)Subjects with events

322 (98.2)

218 (66.5)

327 (99.4)

233 (70.8)

321 (96.1)

209 (62.6)

Alopecia

166 (50.6)

2 (0.6)169 (51.4)

0177 (53.0)

3 (0.9)Anaemia

150 (45.7)

68 (20.7)

155 (47.1)

63 (19.1)

143 (42.8)

52 (15.6)

Nausea151 (46.0)

6 (1.8)150 (45.6)

6 (1.8)152 (45.5)

5 (1.5)

Neutropenia

114 (34.8)

91 (27.7)

124 (37.7)

99 (30.1)

113 (33.8)

88 (26.3)

Fatigue

121 (36.9)

6 (1.8)114 (34.7)

12 (3.6)

109 (32.6)

12 (3.6)

Constipation

114 (34.8)

2 (0.6)98 (29.8)

1 (0.3)

94 (28.1)

3 (0.9)Diarrhoea

83 (25.3)

8 (2.4)

97 (29.5)5 (1.5)63 (18.9)

7 (2.1)

Arthralgia

72 (22.0)

1 (0.3)77 (23.4)

5 (1.5)54 (16.2)

1 (0.3)

Neuropathy peripheral

63 (19.2)

1 (0.3)77 (23.4)

3 (0.9)64 (19.2)

1 (0.3)

Vomiting

87 (26.5)

9 (2.7)77 (23.4)

7 (2.1)

68 (20.4)

7 (2.1)

Peripheral sensory neuropathy

91 (27.7)

075 (22.8)

082 (24.6)

0Abdominal pain

64 (19.5)5 (1.5)64 (19.5)

6 (1.8)58 (17.4)

8 (2.4)Rash

55 (16.8)

2 (0.6)63 (19.1)

7 (2.1)25 (7.5)

1 (0.3)

Thrombocytopenia

47 (14.3)

14 (4.3)

62 (18.8)

25 (7.6)

59 (17.7)

18 (5.4)

Neutrophil count decreased

60 (18.3)

49 (14.9)

54 (16.4)

45 (13.7)

75 (22.5)

59 (17.7)

Decreased appetite

63 (19.2)

1 (0.3)53 (16.1)

1 (0.3)38 (11.4)

1 (0.3)

Myalgia

67 (20.4)

1 (0.3)53 (16.1)

2 (0.6)43 (12.9)

3 (0.9)Cough

35 (10.7)

1 (0.3)51 (15.5)

020 (6.0)0

Dyspnoea

39 (11.9)

3 (0.9)48 (14.6)

4 (1.2)30 (9.0)

1 (0.3)

Headache51 (15.5)

1 (0.3)48 (14.6)

028 (8.4)

0

Urinary tract infection

36 (11.0)

4 (1.2)47 (14.3)

8 (2.4)29 (8.7)

2 (0.6)

Asthenia

34 (10.4)

5 (1.5)46 (14.0)

2 (0.6)22 (6.6)

1 (0.3)Pyrexia37 (11.3)

043 (13.1)

1 (0.3)23 (6.9)

1 (0.3)

Hypomagnesaemia

32 (9.8)

1 (0.3)42 (12.8)

4 (1.2)27 (8.1)

0Insomnia

50 (15.2)

2 (0.6)39 (11.9)

032 (9.6)

2 (0.6)

Platelet count decreased

25 (7.6)

7 (2.1)39 (11.9)

11 (3.3)

44 (13.2)

15 (4.5)

Dizziness

43 (13.1)

1 (0.3)37 (11.2)

1 (0.3)28 (8.4)

0Abdominal pain upper

28 (8.5)

1 (0.3)35 (10.6)

2 (0.6)21 (6.3)

0Infusion related reaction

26 (7.9)

1 (0.3)34 (10.3)

4 (1.2)19 (5.7)0Pruritus

36 (11.0)034 (10.3)

1 (0.3)19 (5.7)

0

Hypothyroidism

28 (8.5)033 (10.0)

04 (1.2)0White blood cell count decreased

32 (9.8)

23 (7.0)31 (9.4)

18 (5.5)

34 (10.2)

17 (5.1)

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Final Clinical Study Report
Protocol JAVELIN OVARIAN 100 (B9991010)
Table S5. 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
Chemotherapy ->Avelumab(N=328)Chemotherapy +Avelumab -> Avelumab(N=329)Chemotherapy ->Observation(N=334)Preferred Term

Pain in extremity

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

27 (8.2)

1 (0.3)30 (9.1)

037 (11.1)

0

The denominator to calculate percentages is N, the number of subjects in the safety analysis set within each treatmentgroup.
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.
Adverse events are sorted by descending frequency of PT in 'Chemotherapy + Avelumab -> Avelumab' treatment group.
MedDRA (v21.1) coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 14MAY2019 (23:39) Source Data: ADAE Output File:./B9991010_restricted/B9991010_CSR/adae_s999a Date of Generation: 07JUN2019 (02:43)
Table 14.3.1.2.4 is for Pfizer internal use.

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Final Clinical Study Report
Protocol JAVELIN OVARIAN 100 (B9991010)
Table S6. Summary of Most Common Serious TEAEs (Any Grade in ≥2% Subjects orGrade ≥3 in ≥2% Subjects in Any Treatment Group), by PT and Maximum
CTCAE Grade During the On-Treatment Period - Safety Analysis Set
Chemotherapy -> Avelumab Chemotherapy + Avelumab (N=328)> Avelumab(N=329)Chemotherapy ->Observation(N=334)Preferred Term
All Grades(n %)Grade ≥ 3(n %)All Grades(n %)Grade ≥ 3(n %)All Grades(n %)Grade ≥ 3(n %)Subjects with events89 (27.1)

69 (21.0)

115 (35.0)

92 (28.0)

63 (18.9)

48 (14.4)

Pyrexia

6 (1.8)0

10 (3.0)

1 (0.3)2 (0.6)

1 (0.3)Anaemia

6 (1.8)4 (1.2)8 (2.4)5 (1.5)6 (1.8)3 (0.9)Febrile neutropenia

10 (3.0)

9 (2.7)8 (2.4)8 (2.4)7 (2.1)6 (1.8)Urinary tract infection

7 (2.1)4 (1.2)7 (2.1)6 (1.8)2 (0.6)2 (0.6)Ileus

3 (0.9)1 (0.3)3 (0.9)2 (0.6)9 (2.7)5 (1.5)The denominator to calculate percentages is N, the number of subjects in the safety analysis set within each treatmentgroup.
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.
Adverse events are sorted by descending frequency of PT in 'Chemotherapy + Avelumab -> Avelumab' treatment group.
MedDRA (v21.1) coding dictionary and CTCAE version 4.03 applied.
PFIZER CONFIDENTIAL SDTM Creation: 14MAY2019 (23:39) Source Data: ADAE Output File:./B9991010_restricted/B9991010_CSR/adae_s999c Date of Generation: 07JUN2019 (03:24)
Table 14.3.2.2.1.1 is for Pfizer internal use.

Based on the irAE case definition and subsequent medical review, patients who received
chemotherapy with avelumab followed by avelumab maintenance most frequently
experienced irAEs, irAEs considered Grade ≥3, and serious irAEs. Only 1 Grade 4 irAE
occurred (PT of type 1 diabetes mellitus); no Grade 5 irAEs occurred. Immune-related AEs
were experienced by 53 patients (16.2%) who received chemotherapy alone followed by
avelumab maintenance and 92 patients (28.0%) who received chemotherapy with avelumab
followed by avelumab maintenance. These irAEs were considered to be Grade ≥3 in
10 patients (3.0%) who received chemotherapy alone followed by avelumab maintenance and24 patients (7.3%) who received chemotherapy with avelumab followed by avelumab
maintenance. Serious irAEs were experienced by 7 patients (2.1%) who received
chemotherapy alone followed by avelumab maintenance and 15 patients (4.6%) who received
chemotherapy with avelumab followed by avelumab maintenance.

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The most frequently reported irAEs (any grade) were from the clusters of immune-related
rash and immune-related endocrinopathies: thyroid disorders (17 patients [5.2%] and27 patients [8.2%] who received chemotherapy alone followed by avelumab maintenance,and 38 patients [11.6%] and 37 patients [11.2%] who received chemotherapy with avelumab
followed by avelumab maintenance).
Based on case definition, IRRs were experienced by 58 patients (17.7%) who received
chemotherapy alone followed by avelumab maintenance and 65 patients (19.8%) who
received chemotherapy with avelumab followed by avelumab maintenance compared with
44 patients (13.2%) who received chemotherapy alone followed by observation. These IRRs
were considered to be Grade ≥3 in 2 patients (0.6%) who received chemotherapy alone
followed by avelumab maintenance and 6 patients (1.8%) who received chemotherapy withavelumab followed by avelumab maintenance compared with 6 patients (1.8%) who received
chemotherapy alone followed by observation. Serious IRRs occurred infrequently and wereexperienced by 2 patients (0.6%) who received chemotherapy alone followed by avelumab
maintenance and 6 patients (1.8%) who received chemotherapy with avelumab followed by
avelumab maintenance. No patients who received chemotherapy alone followed byobservation experienced a serious IRR.
The proportions of patients who had any grade and Grade 3 hematology abnormalities was
similar across all 3 treatment arms for anemia (all grades: 93.3% to 95.1%; Grade ≥3: 19.2%
to 22.4%), platelet count decreased (all grades: 61.0% to 66.9%; Grade ≥3: 6.1% to 11.6%),
and neutrophil count decreased (all grades: 76.7% to 81.0%; Grade ≥3: 44.2% to 48.8%).
For lymphocyte count decreased, Grade ≥3 events were reported by 19.3% of patients who
received chemotherapy with avelumab followed by avelumab maintenance, 10.7% of patients
who received chemotherapy alone followed by avelumab maintenance, and 8.8% of patients
who received chemotherapy alone followed by observation where as the proportion reporting
all grades for this hematological abnormality was similar between all treatment arms (55.5%
to 63.5%).
There were no clinically relevant differences in the proportions of patients who had all grades
and Grade ≥3 chemistry abnormalities across all 3 treatment arms for creatinine increased(all grades: 82.6% to 88.6%; Grade ≥3: 0.0% to 2.1%), serum amylase increased (all grades:
16.3% to 28.3%; Grade ≥3: 1.6% to 3.1%) and lipase increased (all grades: 26.5% to 31.0%;
Grade ≥3: 3.4% to 7.4%). Overall, the proportions of patients who had liver function test
abnormalities was similar across all 3 treatment arms. Of these patients, none met the criteria
for a potential Hy’s Law case (ie, concurrent alanine aminotransferase [ALT] or aspartate
aminotransferase [AST] ≥3 × upper limit of normal [ULN] and total bilirubin ≥2 × ULN andalkaline phosphatase ≤2 × ULN or missing).
Conclusions:

The study did not meet its primary objective and failed to demonstrate that either
platinum-based chemotherapy alone followed by avelumab maintenance or avelumab in
combination with platinum-based chemotherapy followed by avelumab maintenance wassuperior to platinum-based chemotherapy alone followed by observation in prolonging
PFS in patients with previously untreated EOC.
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

The OS data were immature at the time of the analysis and no definitive conclusions canbe drawn.



No apparent benefit on OR, DR, maintenance PFS time, or pCR was observed in either
experimental arm compared to the control arm.



The safety profile of avelumab administered either at maintenance following
chemotherapy (carboplatin and paclitaxel) alone or in combination with chemotherapy
and at maintenance as treatment for patients with EOC was generally tolerable,
manageable, and consistent with the known safety profiles of avelumab andchemotherapy when administered as monotherapies.

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