Public Disclosure Synopsis
Protocol B7391003 – 15 November 2018 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
COMPOUND NUMBER: PF-06439535
PROTOCOL NO.: B7391003
PROTOCOL TITLE: A Phase 3 Randomized, Double-Blind Study of PF-06439535 Plus
Paclitaxel-Carboplatin and Bevacizumab Plus Paclitaxel-Carboplatin for the First-Line
Treatment of Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer

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Study Centers: A total of 159 centers randomized patients into the study: Australia (3),Brazil (11), Bulgaria (1), Chile (3), Croatia (1), Czech Republic (3), France (4),Germany (13), Greece (8), Hungary (7), India (5), Italy (3), Japan (13), Korea (4),Malaysia (2), Netherlands (2), Philippines (2), Poland (9), Romania (7), RussianFederation (17), South Africa (3), Spain (6), Taiwan (1), Thailand (5), Turkey (9),Ukraine (10), and United States (US) (7).
Study Initiation Date and Primary Completion or Final Completion Dates: 20 April
2015 (First Subject First Visit), 08 May 2017 (Primary Completion Date), 22 December 2017
(Last Subject Last Visit).
Phase of Development:
Phase 3
Study Objectives:
Primary Objective

To compare the confirmed objective response rate (ORR) by Week 19 following
treatment with PF-06439535 in combination with paclitaxel and carboplatin to
bevacizumab-European Union (EU) plus paclitaxel and carboplatin in patients who
had not received previous treatment for advanced non-small cell lung cancer(NSCLC).

Secondary Objectives
To evaluate the safety of PF-06439535 plus paclitaxel and carboplatin andbevacizumab-EU plus paclitaxel and carboplatin;

To evaluate secondary measures of tumor control;To evaluate the population pharmacokinetics (PK) of PF-06439535 andbevacizumab-EU;

To evaluate the immunogenicity of PF-06439535 and bevacizumab-EU.

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METHODS
Study Design:This study was a multinational, double-blind, randomized, parallel-group Phase 3 clinical
trial comparing the efficacy and safety of PF-06439535 plus paclitaxel and carboplatin versus
bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for patients withadvanced (unresectable, locally advanced, recurrent or metastatic) non-squamous NSCLC.

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Approximately 355 patients were planned to be enrolled in each treatment arm for a total of
approximately 710 patients at over 300 centers; up to approximately 10% additional patients
may have been enrolled due to operational/logistical considerations. Patients wererandomized (1:1) to receive at least 4 cycles and no more than 6 cycles of either
PF-06439535 plus paclitaxel and carboplatin or bevacizumab-EU plus paclitaxel andcarboplatin, followed by the previously assigned blinded bevacizumab monotherapy.
Randomization was stratified by region (according to the location of the drug depot
supplying the site), sex (male/female) and smoking history (never/ever). The estimatedduration of study participation was approximately 1 year. Last subject last visit (LSLV) was
defined as up to 1 year from randomization of the last patient (End of Treatment) plus 28-day
follow-up. The study was considered complete (End of Study) when the last patient hadcompleted the LSLV. See study schema (Figure 1) for details.
Figure 1. Study Schema

Bevacizumab-Pfizer stands for PF-06439535.
Abbreviation: EU=European Union.
* Assigned bevacizumab monotherapy: Following completion of at least 4 cycles and no more than 6 cycles ofchemotherapy.

The schedule of activities (SOA) is presented in Table 1.

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Table 1.

Schedule of Activities

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Treatment Period (Combination Therapy)
Blinded bevacizumab with chemotherapy

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Screening
Protocol Activity/Cycle(1 Cycle=21 days)

28 days
prior torandomization

Cycle
1

Cycle
2

Cycle
3

Cycle
4

Cycle
5

Cycle
6

-4

0

4

4

4

4

4

Study Visit Window (Days)
Pre-treatment Documentation
Informed consent3
X
Demography, medical/cancerXhistory, mutation status4
Complete physicalX
examination5
6
Brief physical examination
7

Vital signs

X

Baseline signs and symptoms8
ECOG performance status
Inclusion/exclusion criteria

X

X
X

X
X

X
X

X
X

Through Cycle 17(Up to week 52)

Cycle 18+
1 year post-randomization1

4

4

End of Treatment/
Withdrawals2

7X

Per local standard of care

X

X

Per local standard of careX

Per local standard of care

X

X

X

X

X

X

X

Per local standard of care

X

X

X

X

X

X

X

X

Per local standard of care

X

X

Per local standard of care

X
X
X
X

X

Laboratory Studies and Tests
Hematology10
X
11

X

X

Treatment Period(Monotherapy)
Blinded bevacizumab

X
X

9

X

Treatment Period(Monotherapy)
Blinded bevacizumab

Blood chemistryX

Coagulation12
Pregnancy test13

X
(X)13

X

X

X

X

X

X

X

Per local standard of care
Per local standard of care

Urinalysis14

X

X

X

X

X

X

X

X

Per local standard of care

Serological tests15

(X)
X

X

X

X

X

X

X

X

X

X

X

X

X

X

Immunogenicity (ADA/NAb)16
17

Pharmacokinetics

X

X

X

X

X

X

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Table 1.

Schedule of Activities (Continued)

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Treatment Period (Combination Therapy)
Blinded bevacizumab with chemotherapy

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Screening
Protocol Activity/Cycle(1 Cycle=21 days)

Study Visit Window (Days)
Tumor Assessments
Brain scan18
CT or MRI of chest, abdomen,
and other disease sites18
Randomization
Randomization19

28 days
Cycle Cycle Cycle Cycle
prior to1
2
3
4
randomization
0
-4
4
4
4
X
X

Cycle
5

Cycle
6

4

4

Treatment Period(Monotherapy)
Blinded bevacizumab

Treatment Period(Monotherapy)
Blinded bevacizumab

Through Cycle 17(Up to week 52)

Cycle 18+
1 year post-randomization1

4

4

As clinically indicated and at time of confirmatory scan for PR/CR
Every 6 weeks (7 days) until Week 25 (based on date of randomization);
After Week 25, every 9 weeks (7 days) until 1 year from randomization

End of Treatment/
Withdrawals2

7

Per local standard of care
Per local standard of care

X

X

Drug Administration
Paclitaxel and carboplatin20
Blinded bevacizumab21

X
X

X
X

X
X

X
X

Optional Optional
X
X
X

X

Other Clinical Assessments
12-lead ECG22XXMUGA or ECHO23

X

X

24

Contraception check

X

AEs25

X

Prior medications/treatments26

X

Concomitant treatments27

X
X
X
X
Monitored continuously

X

X

X

Per local standard of care

X

Monitored continuously

28

Survival follow-up
Every 2 months (14 days) from last study drug administration
Abbreviations: ADA=anti-drug antibody, AE=adverse event, ALK=anaplastic lymphoma kinase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=bloodurea nitrogen, CR=complete response, CRF=case report form, CT=computed tomography, ECG=electrocardiogram, ECHO=echocardiogram, ECOG=Eastern Cooperative
Oncology Group, EGFR=epidermal growth factor receptor, EML4=echinoderm microtubule-associated protein-like 4, INR=international normalized ratio, LVEF=left ventricularejection fraction, MRI=magnetic resonance imaging, MUGA=multi gated acquisition scan, NAb=neutralizing antibody, PK=pharmacokinetic(s), PR=partial response,
SAE=serious adverse event.

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Table 1.

Schedule of Activities (Continued)

Page 3 of 4
1. One (1) year post-randomization: Patients who continued to receive study treatment after 1 year had assessments performed according to local standard of care; reduced
data collection, although tumor assessment and safety data collection were required.
2. End of Treatment/withdrawals: When patients discontinued all study treatment, patients were require to be evaluated 28 (+7) days after last dose or prior to the start of new
anti-cancer therapy if initiated within 28 days after the last dose.
3. Informed consent: Had to be obtained prior to undergoing any study specific procedure and could occur prior to the 28-day screening period.
4. Demographics and medical/cancer history: Included information on prior anti-tumor regimens (including chemotherapy and radiation therapy and duration of treatment),
mutation test results, if known, and progression or relapse date. Testing for mutations was not required, however, patient records were reviewed for known sensitizing
EGFR mutations (for example, exon 19 deletion or exon 21 L858R) or EML4-ALK translocation positive mutations. If mutation testing was performed, samples wererequired to be tested by local approved laboratories, and the results were required to be reviewed and confirmed as negative for mutations prior to randomization.
5. Physical examination: Included head, ears, eyes, nose, mouth, skin, neck, heart and lung examinations, lymph nodes, abdomen, musculoskeletal, neurological systems, andweight. Height was recorded at Screening only. Genitourinary examination was only required if directed by signs or symptoms.
6. Brief physical examination: Performed as directed by signs and symptoms on Day 1 (pre-dose) of each cycle after Screening.
7. Vital signs: Temperature was required to be taken using the same method throughout the study. Blood pressure, heart rate, and respiratory rate were required to be takenwith the patient in the supine or sitting position after the patient had been resting quietly for at least 5 minutes and prior to dosing on dosing days. Weight was required tobe taken at the beginning of each cycle and was to be used for dose calculation. On days of an infusion, vital signs were required to be taken within 30 minutes before thefirst infusion and within 30 minutes of the end of the last infusion.
8. Baseline signs and symptoms: Observed after Screening and before Cycle 1, Day 1 pre-dose were recorded as part of medical history or as brief physical examination
findings.
9. Inclusion/exclusion criteria: Eligibility criteria were reviewed to confirm eligibility prior to randomization.
10. Hematology: Tests included hemoglobin, white blood cells, platelets, and absolute neutrophil count. Results of tests had to be reviewed prior to each cycle of therapy.
11. Chemistry: Tests included ALT, AST, alkaline phosphatase, total bilirubin, serum or plasma creatinine, sodium, potassium, total calcium, BUN or urea, magnesium, andalbumin, and results had to be reviewed prior to each cycle of therapy.
12. Coagulation: Tests included INR for prothrombin time (or prothrombin time if INR was not available) and activated partial thromboplastin time. Tests may have been
performed more frequently if clinically indicated. Results of tests had to be reviewed prior to dosing on Cycle 1 Day 1.
13. Pregnancy test: For female patients of childbearing potential, a serum or urine pregnancy test with sensitivity of at least 25 mIU/mL was performed by the local certified
laboratory, and 2 negative tests were required before receiving the first dose of investigational product. The second negative test was required to be done during the first
5 days of the menstrual period, immediately preceding the first dose of any study treatment.
14. Urinalysis: If the results of the dipstick urine protein indicated 2+ proteinuria, follow-up was required to be performed with a quantitative urine protein analysis according
to local standard practices with data captured on the AE CRF if AE criteria were met. The results of the dipstick had to be reviewed prior to each cycle of therapy.
15. Serological tests (optional): If testing was performed, samples had to be tested by local approved laboratories, and the results had to be reviewed and eligibility confirmedprior to randomization.
16. Immunogenicity: Blood sampling for ADA/NAb prior to blinded bevacizumab. If AEs were considered possibly related to ADA formation, an additional sample may havebeen collected at the time of the immunogenicity-related AEs.
17. PK: Blood sampling for drug concentration prior to blinded bevacizumab. Post-dose samples were also collected at 1 hour (0.5 hour) after the end of blinded
bevacizumab for Cycles 1 and 5 (if patient received Cycle 5). If ADA/NAb sampling was conducted at the time of immunogenicity related AEs, a serum sample for drugconcentration was also collected at that same time point.

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Table 1.

Schedule of Activities (Continued)

Page 4 of 4
18. Tumor assessments: Assessments had to include CT with contrast or MRI of head, chest, abdomen (including adrenals) and other disease sites such as pelvis if clinicallyindicated. Tumor assessments were not scheduled based on cycle length or number of cycles received. Assessment delay to conform to treatment delays was not
permitted. The same method of tumor assessments was to be used throughout the trial. A confirmatory scan was required approximately 6 weeks (+7 days) for a CR/PR.
19. Randomization: Unless clinically indicated, screening physical examination and laboratory assessments including blood chemistry, hematology, and urinalysis, were notrequired to be repeated for randomization if they were performed 7 days prior to Cycle 1, Day 1, and results met eligibility criteria. Eligibility criteria were reviewed andSponsor confirmation of eligibility must have been received prior to randomization. Randomization was required on Day 1 of first dose (but no more than 1 day prior).
20. Paclitaxel and carboplatin administration: Per dosing algorithm for a total of at least 4 cycles and no more than 6 cycles. Premedication was to be administered according
to the local label or institutional guidelines. Dose delay (up to 2 weeks) and dose reduction were permitted per local guidelines.
21. Blinded bevacizumab: 15 mg/kg by intravenous infusion on Day 1 of each of the 3-week (21-day) cycles.
22. ECG: 12-lead ECG was obtained at Screening, as clinically indicated, and at the End of Treatment Visit.
23. MUGA or ECHO: To assess LVEF; the original methodology used for each patient had to be used throughout the trial.
24. Contraception check: Male patients who were able to father children and female patients who were of childbearing potential needed to affirm that they met the criteria forcorrect use of 2 of the selected methods of contraception.
25. AEs: Patients had to be followed for AEs from the first day of study treatment through the patient’s last visit and at least 28 days after the last dose of study treatment, or
until all serious or study drug-related toxicities had resolved or were determined to be “chronic” or “stable”, whichever was later as assessed by the investigator. SAEs
were required to be monitored and reported from the time that the patient provided informed consent through and including 28 calendar days after the last study treatment.
SAEs considered related to study treatments were to be reported whenever they occurred even after 28 days after the last study treatment.
26. Prior medication/treatments: Medications and non-drug treatments delivered prior to initial dosing were recorded from 28 days prior to the start of study treatment.
27. Concomitant treatments: Recorded from initial dosing and monitored continuously by the investigator until at least 28 days following the last dose of study treatment tocoincide with the safety evaluation period. Patients discontinuing the active treatment phase were to enter the follow-up phase during which survival and new anti-cancer
therapy information were to be collected until the study was completed or was terminated early.
28. Survival follow-up: After discontinuation from treatment, survival status was to be collected by telephone contact every 2 months (14 days) until death or 1 year frompatient randomization.

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Number of Patients (Planned and Analyzed): Approximately 355 patients were planned to
be enrolled in each treatment arm for a total of approximately 710 patients; up to
approximately 10% additional patients may have been enrolled due to operational/logisticalconsiderations.

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Overall, a total of 719 patients were randomized to the study, 358 patients to the
PF-06439535 group and 361 patients to the bevacizumab-EU group. Of these, 714 patients
received at least 1 dose of study drug or chemotherapy, 356 patients were assigned to the
PF-06439535 group and 358 patients were assigned to the bevacizumab-EU group.
Diagnosis and Main Criteria for Inclusion and Exclusion: Male and female patients
18 years of age, or age of consent in the region, who had histologically or cytologicallyconfirmed diagnosis of predominately non-squamous NSCLC and newly diagnosed
Stage IIIB or IV NSCLC (according to Revised International System for Staging Lung
Cancer Criteria of 2010) or recurrent NSCLC were eligible to participate in the study.
Patients who had 1) small cell lung cancer (SCLC) or combination of SCLC and NSCLC,
squamous-cell tumors and mixed adenosquamous carcinomas of predominantly squamous
nature, 2) evidence of a tumor that compressed or invaded major blood vessels or tumor
cavitation that was likely to bleed, 3) known sensitizing epidermal growth factor receptor(EGFR) mutations (for example, exon 19 deletion or exon 21 L858R) or echinoderm
microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK)translocation positive mutations, 4) prior systemic therapy for NSCLC (except forneoadjuvant or adjuvant therapy prior to surgical resection for primary disease), wereineligible to participate in this study.
Study Treatment: On treatment days when both bevacizumab and paclitaxel-carboplatinwere administered, the order of administration was: 1) paclitaxel, 2) carboplatin,
3) bevacizumab. Bevacizumab monotherapy was administered following completion of atleast 4 cycles and no more than 6 cycles of chemotherapy.
Premedication to ameliorate the toxicities associated with the chemotherapy were to beadministered according to the local label or institutional guidelines.
Paclitaxel:
Following premedication, paclitaxel was administered as the first drug when chemotherapy
was administered. Paclitaxel at a dose of 200 mg/m2 was administered by intravenous (IV)infusion over 3 hours on Day 1 in each cycle (21-day cycle). In the absence of progressive
disease (PD), patients received paclitaxel treatment for at least 4 cycles but no more than
6 cycles. Dose reduction for toxicity was allowed.
Carboplatin:
Carboplatin was administered by IV infusion over a minimum of 15 minutes, and could be
administered immediately after the paclitaxel infusion had completed. Patients wereadministered carboplatin for at least 4 cycles and no more than 6 cycles. Dose reduction for
toxicity was allowed.

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Bevacizumab:
Blinded bevacizumab was administered once at the start of every 21-day cycle. The initial
dose was 15 mg/kg delivered over 90 minutes as an IV infusion. If the first infusion was
well tolerated, the second infusion may have been administered over 60 minutes. If the
60-minute infusion was well tolerated, all subsequent infusions may have been administeredover 30 minutes. If during the shortened infusions, infusion related reactions (IRRs)
occurred, the duration of the infusion could be increased at the discretion of the investigator.
For the infusion of bevacizumab in patients over 110 kg, the dilution volume and infusion
time were to be increased. The concentration of bevacizumab solution was required to be
kept within the range of 1.4 mg/mL to 16.50 mg/mL.
Infusions were not allowed to be administered as an IV push or bolus injection. Infusions
were not allowed to be administered or mixed with dextrose solutions.

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Assigned blinded bevacizumab monotherapy could be administered after chemotherapy had
been discontinued until Response Evaluation Criteria in Solid Tumors (RECIST)
version 1.1 defined disease progression, unacceptable toxicity, discretion of the investigator,
regulatory request, death, withdrawal of consent occurred, or End of Treatment, whichevercame first.
Efficacy, Safety, Pharmacokinetic and Immunogenicity Endpoints:
Efficacy Endpoints:
The primary efficacy endpoint is:ORR, evaluating the best response achieved by Week 19 and subsequently confirmed by
6 weeks thereafter, in accordance with RECIST version 1.1.

The secondary efficacy endpoints are:

Duration of response (DOR), 1 year progression-free survival (PFS) rate and 1-year
survival rate from randomization.

PK Endpoints:
The secondary PK endpoints are:

Peak and trough bevacizumab-Pfizer and bevacizumab-EU concentrations at selected
cycles up to 1 year from randomization;

Immunogenicity Endpoints:
The secondary immunogenicity endpoints are:

Incidence of anti-drug (bevacizumab) antibodies (ADA), including neutralizing
antibodies (NAb) up to 1 year from randomization.

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Safety Endpoints:
The secondary safety endpoints are:

Safety characterized by type, incidence, severity, timing, seriousness, and relationship to
study therapy of adverse events, including cardiotoxicity and infusion-related reactions,and laboratory abnormalities at 1 year from randomization.

Safety Evaluations:
Safety evaluations were assessed by adverse event (AE) and serious adverse event (SAE)
monitoring, clinical safety laboratory assessments, vital signs, physical examinations, and12-lead electrocardiogram (ECG) monitoring.
Statistical Methods:
Efficacy:

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Analysis Populations:
The Intent-to-Treat (ITT) population was defined as all patients who were randomized to
study treatment. The ITT population was used for patient accountability and all efficacy
analyses.
The Per-Protocol (PP) population was defined as all patients who were randomized andreceived the study treatment (PF-06439535 or bevacizumab-EU) as planned and had no
major protocol deviations. The PP population was used for sensitivity analyses of the
primary and secondary endpoints.
Analyses of the Primary Efficacy Endpoint:
The two 1-sided hypotheses were tested in this study for ORR in order to show that
PF-06439535 was equivalent to bevacizumab-EU.
For the US Food and Drug Administration (FDA), equivalence was considered established if
the 90% confidence interval (CI) of the risk ratio falls into the margins of (0.73, 1.37).
For Japan Pharmaceuticals and Medical Devices Agency (PMDA), equivalence wasconsidered established if the 95% CI of the risk ratio falls into the margins of (0.729, 1.371).
For the EU European Medicines Authority (EMA), equivalence was considered established if
the 95% CI of the risk difference falls into the margins of (-13%, 13%).
The primary efficacy analysis for the primary endpoint in the ITT population was based on
the Miettinen and Nurminen (1985) method without strata. Estimated risk ratio and risk
difference and the asymptotic 95% and 90% CIs in ORR between PF-06439535 andbevacizumab-EU were computed. These values were used to determine equivalence basedon the criteria defined above.

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The same analysis based on PP population was also performed as a sensitivity analysis.
Descriptive statistics (frequency and percentage) for complete response (CR), partial
response (PR), and ORR were presented by treatment group, with 95% CI being determinedbased on the F-distribution.
Analyses of the Secondary Efficacy Endpoints
For PFS, survival (time to death), and DOR, a Cox proportional hazard model was used foranalysis; the model included treatment and the covariates (region, gender and smoking
history). The hazard ratios and the 95% CIs of the hazard ratios based on the model were
presented.
All analyses described in this section were performed with the ITT population. As sensitivity
analyses, these analyses were also repeated with the PP population.

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Duration of Response (DOR)

DOR was defined as the time from date of the first documentation of objective tumor
response (CR or PR) to the first documentation of PD or to death due to any cause in theabsence of documented PD. DOR was only calculated for the subgroup of patients with aconfirmed objective response achieved by Week 19 from ITT population, the same analysis
was repeated for PP population as a sensitivity analysis.
Censoring for the DOR endpoint was assigned on the date of the last tumor assessment if noassessment of tumor progression was identified and the patient did not die while on study. If
there was no adequate disease assessment at baseline, the endpoint was to be censored on thedate of randomization with duration of 1 day. When a patient had missing tumor
assessment(s) but remained as a CR or PR responder at the time of data analysis, theendpoint was to be censored at the time of the last available tumor assessment where CR or
PR was declared.
The Kaplan-Meier method was used to estimate the DOR rate at 1-year. The 2-sided
95% CIs of the rate using the Greenwood’s formula was reported. Kaplan-Meier curves
were also plotted for each of the 2 treatment groups at 1-year together with a 2-sided log-rank
test stratified by region, gender and smoking history to compare the DOR curve between the
2 treatment groups at 1-year. The Kaplan-Meier method was also used to obtain theestimates of median DOR associated with each treatment group. The 2-sided 95% CIs forthe 25th, 50th and 75th percentiles of the DOR time using the Brookmeyer and Crowley
method were to be reported when estimable.
Progression-free Survival (PFS) and PFS Rates

PFS was defined as the time from date of randomization to first progression of disease ordeath due to any cause, whichever occurred first. The tumor assessment was based oninvestigator assessment in accordance with RECIST version 1.1.
Similar Kaplan-Meier analyses, as described for DOR, were carried out for PFS.
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Survival and Survival Rates

Survival (time to death) was defined as the time from date of randomization to death due toany causes. Patients were censored for this endpoint on the date last known alive. Date oflast known alive could be determined from survival follow-up data, onset date of AE,
concomitant medication or any other documented assessments. The Kaplan-Meier method
was used to estimate 1-year survival rates, the 2-sided 95% CIs of 1-year survival rate wasalso reported. Kaplan-Meier curves were also plotted for each of the 2 treatment groups at
1-year together with a 2-sided log-rank test stratified by region, gender and smoking history
to compare the survival distribution between the 2 treatment groups at the 3 time points.
Safety:The safety population was defined as all patients who were randomized and received at least
1 dose of study treatment. Safety evaluations were summarized in accordance with sponsor’s
reporting standards.

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Pharmacokinetics:
Patients in the PP population who had at least 1 drug concentration measurement post
administration of treatment were included in the PK analysis.
The drug concentration-time data were summarized by descriptive statistics (mean, standard
deviation [SD], median, minimum, and maximum) according to treatment. A listing of allconcentrations sorted by treatment, patient identification number (ID) and nominal timepost-dose was generated. The concentration listing also included the actual sampling times.
Deviations from the nominal time were given in a separate listing.
Immunogenicity:
The safety population was used for ADA and NAb analyses. The percentage of patients withpositive ADA and NAb was summarized for each treatment and each visit. For patients withpositive ADA, the magnitude (titer), time of onset, and duration of ADA response were also
described, if data permitted.
RESULTS
Patient Disposition and Demography:
The ITT population was comprised of 719 patients who were randomized to double-blind
treatment, 358 patients to the PF-06439535 group and 361 patients to the bevacizumab-EUgroup (Table 2). Of these, 714 patients were included in the safety population and received
at least 1 dose of study drug or chemotherapy, 356 patients were assigned to the
PF-06439535 group and 358 patients were assigned to the bevacizumab-EU group.
Five (5) patients did not receive any blinded bevacizumab and paclitaxel/carboplatin,
including 2 patients randomized to the PF-06439535 group, and 3 patients randomized to thebevacizumab-EU group.

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Efficacy evaluations were performed using the ITT population (the primary population). The
PP population was used for sensitivity analyses of the primary and secondary efficacy
endpoints. PK parameters were analyzed using the PK population. The safety population
was used for all safety endpoints, including ADA and NAb analyses. There were comparable
numbers of patients in the 2 treatment groups.
Table 2.

Patient Disposition

Number (%) of Patients

PF-06439535

Bevacizumab-EU

Total

358

361

719

Treated356 (99.4)

358 (99.2)

714 (99.3)

Study
Discontinued
Randomized not treated356 (99.4)
2 (0.6)358 (99.2)
3 (0.8)714 (99.3)
5 (0.7)

Treatment
Discontinuedb

356 (99.4)

358 (99.2)

714 (99.3)

Analyzed for efficacy
ITT population
PP population
PK population

358 (100.0)
351 (98.0)
351 (98.0)

361 (100.0)355 (98.3)
354 (98.1)

719 (100.0)
706 (98.2)
705 (98.1)

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Randomizeda

Analyzed for safety
Safety populationc
356 (99.4)
358 (99.2)
714 (99.3)
AEs
356 (100.0)
358 (100.0)
714 (100.0)
Laboratory data
342 (96.1)
348 (97.2)
690 (96.6)
Abbreviations: AE=adverse event, EU=European Union, ITT=Intent-to-Treat, PK=pharmacokinetic,
PP=Per-Protocol.
a. The number of randomized patients was used as the denominator for percentages except for safety data.
b. Treatment was defined as all 3 agents (blinded bevacizumab, paclitaxel and carboplatin).
c. The number of safety population was used as the denominator for percentages of AEs and laboratorydata.

Of the 719 patients randomized to the study, 467 were male and 252 were female. The mean
(SD) age was 61.3 (9.2) years, 58.4% were 45 to 64 years of age, 36.6% were 65 years ofage, and the remaining 5.0% were 18 to 44 years of age. The majority of patients were ofWhite race (88.7%), 10.6% were of Asian race and included patients from the Indian
subcontinent, China, Japan and Korea.
Histopathological classifications for the primary diagnosis of the 719 randomized patientswere adenocarcinoma (699 [97.2%] patients), large cell carcinoma (11 [1.5%] patients),
mixed adenocarcinoma (7 [1.0%] patients), and other (2 [0.3%] patients including
1 neuroendocrine carcinoma and 1 other-non-squamous NSCLC). The majority of patients
had newly diagnosed Stage IV disease and 13.2% of patients presented at Screening withrecurrent disease. Of the 719 patients who were randomized to the study, 129 (17.9%)
patients had received prior resection of primary disease (not including biopsies), 35 (4.9%)
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Protocol B7391003 – 15 November 2018 - Finalradiation therapy, for their primary diagnosis, which were comparable for both treatmentgroups. Of the 719 patients who were randomized to the study, the most common previous
systemic therapies were cisplatin (28 [3.9%] patients) and vinorelbine (20 [2.8%] patients),
both of which were reported with comparable proportions in the 2 treatment groups. The
most frequently reported histology classification was adenocarcinoma (348 [97.2%] and351 [97.2%] patients for the PF-06439535 and bevacizumab-EU groups, respectively), andthe median duration of disease since primary diagnosis of NSCLC was 1.2 months (range:
0.2 to 210.9 months) and 1.3 months (range: 0.1 to 137.9 months) for the PF-06439535 andbevacizumab-EU groups, respectively.
Efficacy, Pharmacokinetic, and Immunogenicity Results:
Primary Efficacy Endpoint:

090177e18fc424a7\Approved\Approved On: 19-Nov-2018 01:25 (GMT)The primary efficacy endpoint of the study was ORR defined as the percent of patients
within each treatment group who achieved a best overall response (BOR) of CR or PR by
Week 19, in accordance with RECIST version 1.1, and subsequently confirmed on afollow-up tumor assessment by Week 25. The primary endpoint of ORR was based on theSponsor’s derived BOR using tumor measurements reported by the investigator in the casereport form (CRF).
A summary of the BOR and ORR for the ITT population is provided in Table 3. In the
PF-06439535 treatment group, 9 patients (2.5%) had CR, 153 patients (42.7%) had PR,
154 patients (43.0%) had stable disease, and 15 patients (4.2%) had PD. In thebevacizumab-EU treatment group, the corresponding numbers of patients were 4 (1.1%) had
CR, 157 (43.5%) had PR, 167 (46.3%) had stable disease, and 14 (3.9%) had PD. Overall,
46 patients (6.4%) were considered not evaluable for response (27 [7.5%] and 19 [5.3%] in
the PF-06439535 and bevacizumab-EU groups, respectively) due to early death, unevaluable
tumor assessment, or early study discontinuations, and were treated as non-responders in the
ORR calculation.
Similarity between PF-06439535 and bevacizumab-EU was statistically demonstrated for the
primary efficacy endpoint, ORR, based on the pre-specified criteria for each of the 3 Health
Authorities. The analysis of ORR showed an un-stratified risk ratio of 1.0146 (PF-06439535
versus bevacizumab-EU), with a 95% CI of (0.8628, 1.1933) and a 90% CI of (0.8856,
1.1625), and an un-stratified risk difference of 0.6531% (PF-06439535 versus
bevacizumab-EU), with a 95% CI of (-6.6080%, 7.9082%), all of which fell entirely within
the equivalence margins.
The BOR distribution and the analysis of ORR for patients in the PP population wereconsistent with that of the ITT population.

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Table 3.

Summary of Best Overall Response and ORR (Week 19) (Unstratified) - ITT
Population

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PF-06439535(N=358)Bevacizumab-EU(N=361)

Total(N=719)

Best overall response, n (%)
9 (2.5)4 (1.1)13 (1.8)
Complete response (CR)
153 (42.7)
157 (43.5)
310 (43.1)
Partial response (PR)154(43.0)
167(46.3)
321 (44.6)
Stable disease
15 (4.2)
14 (3.9)29 (4.0)
Progressive diseasea27 (7.5)
19 (5.3)
46 (6.4)
Not evaluable
162(45.3)
161(44.6)
323(44.9)
Objective response rate (CR + PR), n (%)
b(40.01, 50.57)(39.40, 49.89)(41.25, 48.64)
95% exact CI
Treatment comparison (versus bevacizumab-EU)
0.6531
Un-stratified risk difference in ORR (%)cc(-6.6080, 7.9082)
95% CI of difference (%)
Treatment comparison (versus bevacizumab-EU)
1.0146
Un-stratified risk ratiodd(0.8628,
1.1933)
95% CI of risk ratiod(0.8856, 1.1625)
90% CI of risk ratio
ORR was defined as the percentage of patients within each treatment group who achieved complete response orpartial response by Week 19 of the study in accordance with RECIST version 1.1 which was subsequently
confirmed by Week 25.
Abbreviations: CI=confidence interval, CR=complete response, EMA=European Medicines Authority,
EU=European Union, FDA=Food and Drug Administration, ITT=Intent-to-Treat, n/N=number of patients withobservation/total number of patients, ORR=objective response rate, PMDA=Pharmaceuticals and Medical
Devices Agency, PR=partial response, RECIST=Response Evaluation Criteria in Solid Tumors, US=UnitedStates.
a. Not evaluable: Early death, unevaluable tumor assessment, and early study discontinuations.
b. Exact method based on F-distribution was used.
c. Calculated based on 2-sided Miettinen and Nurminen method without strata for risk difference for
confirmed response. EU EMA equivalence margins (95% CI in -13% to 13%).
d. Calculated based on 2-sided Miettinen and Nurminen method without strata for risk ratio for confirmed
response. US FDA equivalence margins (90% CI in 0.73 to 1.37) and Japan PMDA equivalence margins(95% CI in 0.729 to 1.371).

Secondary Efficacy Endpoints:
Duration of Response (DOR)
The percentage of all patients who achieved objective response (CR or PR) by Week 19 andsubsequently confirmed by Week 25 in the ITT population was comparable between the
2 treatment groups (162 [45.3%] patients in the PF-06439535 group compared with161 [44.6 %] patients in the bevacizumab-EU group) (Table 3). The probability of nothaving subsequent progression or death at Week 55 after a confirmed objective response was
32.0% (95% CI: 24.2%, 40.1%) in the PF-06439535 group, and 30.7% (95% CI: 23.2%,
38.6%) in the bevacizumab-EU group (Table 4).

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Using a Cox proportional hazards model with region, sex and smoking history as strata, thehazard ratio when comparing DOR between PF-06439535 and bevacizumab-EU was 0.800,
with a 95% CI of (0.608, 1.051). The stratified log-rank test resulted in a 2-sided p-value of
0.1077 indicating no statistically significant difference between the 2 treatment groups(Table 4).
The analysis of DOR for patients in the PP population showed consistent results to that of the
primary ITT population.
Table 4.

Duration of Objective Response (Week 55) - Patients in ITT Population Who
Had an Objective Response Achieved by Week 19

Number (%) of Patients

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Patients with event
Type of event
Progressive disease
Death
Number censored
Probability of being event free (95% CIa)
at 55 weeks

PF-06439535(N=162)107 (66.0)

Bevacizumab-EU(N=161)119 (73.9)

Total(N=323)226 (70.0)

101 (62.3)
6 (3.7)55 (34.0)

110 (68.3)
9 (5.6)42 (26.1)

211 (65.3)
15 (4.6)
97 (30.0)

0.320 (0.242, 0.401) 0.307 (0.232, 0.386) 0.315 (0.261, 0.371)

Kaplan-Meier estimates of time to event (weeks)
Quartiles (95% CI)bQ1
25.3 (20.7, 27.1)
18.7 (17.9, 21.3)
21.3 (18.7, 24.4)
Median36.3 (31.6, 43.6)
28.7 (27.0, 36.3)
35.9 (28.7, 36.6)
Q3
69.1 (55.0, 86.1)
62.1 (51.3, 76.6)
65.6 (58.1, 76.6)cStratified analysis
Comparison versus bevacizumab-EU
Hazard ratiod
0.800
d95% CI
0.608, 1.051
2-sided p-valuee
0.1077A hazard ratio=1 indicated no difference in PD/death between PF-06439535 and bevacizumab-EU;>1 indicated an increase in PD/death in PF-06439535;<1 indicated an increase in PD/death in bevacizumab-EU.
Abbreviations: CI=confidence interval, CR=complete response, EU=European Union, ITT=Intent-to-Treat,
N=number of patients who achieved confirmed objective response (CR or PR) by Week 19, PD=progressive
disease, PR=partial response, Q1=25th percentile, Q3=75th percentile.
a. Estimated from the Kaplan-Meier curve; calculated from the product-limit method.
b. Based on the Brookmeyer and Crowley method.
c. Stratified by smoking, sex, and region.
d. Based on the Cox proportional hazards model stratified by smoking, sex, and region.
e. Two-sided p-value from the log-rank test stratified by smoking, sex, and region.

One (1) Year Progression-Free Survival (PFS) Rate
The percentages of patients who progressed/died or were censored in the ITT population
were comparable between the 2 treatment groups. There were 228 (63.7%) and
255 (70.6%) patients who had objective progression or had died without objective
progression in the PF-06439535 group and the bevacizumab-EU group, respectively
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Protocol B7391003 – 15 November 2018 - Final(Table 5). The probability of being progression free at Week 55 was 32.3% (95% CI: 26.9%,
37.8%) in the PF-06439535 group and 30.5% (95% CI: 25.3%, 35.8%) in thebevacizumab-EU group (Table 5).
Using a Cox proportional hazards model with region, gender and smoking history as strata,
the hazard ratio when comparing PFS between PF-06439535 and bevacizumab-EU was
0.931, with a 95% CI of (0.777, 1.116). The stratified log-rank test resulted in a 2-sided
p-value of 0.4492.
The analysis of PFS for patients in the PP population showed results consistent with theprimary ITT population.
Table 5.

Summary of Progression-Free Survival (Week 55) - ITT Population

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Number (%) of Patients
Patients with event
Type of event
Progressive disease
Death
Number censored
Probability of being event free (95% CIa)
at 55 weeks

PF-06439535(N=358)228 (63.7)

Bevacizumab-EU(N=361)255 (70.6)

Total(N=719)483 (67.2)

192 (53.6)
36 (10.1)
130 (36.3)

219 (60.7)
36 (10.0)106 (29.4)

411 (57.2)
72 (10.0)236 (32.8)

0.323 (0.269, 0.378) 0.305 (0.253, 0.358) 0.314 (0.276, 0.352)

Kaplan-Meier estimates of time to event (week)
Quartiles (95% CI)bQ1
23.4 (18.9, 24.3)
24.0 (19.3, 24.3)
23.9 (20.3, 24.1)
Median41.3 (33.1, 42.3)
33.6 (33.0, 37.0)
34.3 (33.1, 41.1)
Q3
71.9 (59.7, 88.3)
68.9 (56.9, 75.0)
69.0 (60.9, 75.0)
Stratified analysiscComparison versus bevacizumab-EU
Hazard ratiod
0.931
95% CId
0.777, 1.116
2-sided p-valuee
0.4492A hazard ratio=1 indicated no difference in PD/death between PF-06439535 and bevacizumab-EU;>1 indicated an increase in PD/death in PF-06439535;<1 indicated an increase in PD/death in bevacizumab-EU.
Abbreviations: CI=confidence interval, EU=European Union, ITT=Intent-to-Treat, N=total number of patients,
PD=progressive disease, Q1=25th percentile, Q3=75th percentile.
a. Estimated from the Kaplan-Meier curve; calculated from the product-limit method.
b. Based on the Brookmeyer and Crowley method.
c. Stratified by smoking, sex and region.
d. Based on the Cox proportional hazards model stratified by smoking, sex and region.
e. Two-sided p-value from the log-rank test stratified by smoking, sex and region.

One (1) -Year Survival Rate
The percentage of patients who died due to all causes in the ITT population was comparable
between the 2 treatment groups. There were 144 (40.2%) and 149 (41.3%) patients who diedin the PF-06439535 group and the bevacizumab-EU group, respectively (Table 6). The
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Protocol B7391003 – 15 November 2018 - Finalprobability of being alive at Week 55 was 65.8% (95% CI: 60.5%, 70.6%) in the
PF-06439535 group, and 64.1% (95% CI: 58.6%, 69.0%) in the bevacizumab-EU group(Table 6).
Using a Cox proportional hazards model with region, sex and smoking history as strata, thehazard ratio when comparing OS between PF-06439535 and bevacizumab-EU, was 0.918,
with a 95% CI of (0.729, 1.157). The stratified log-rank test resulted in a 2-sided p-value of0.4726, indicating no statistically significant difference between the 2 treatment groups(Table 6).
The analysis of OS for patients in the PP population showed consistent results to that of the
primary ITT population.
Table 6.

Summary of Overall Survival (Week 55) - ITT Population
PF-06439535(N=358)144 (40.2)
214 (59.8)

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Number (%) of Patients

Bevacizumab-EU(N=361)149 (41.3)
212 (58.7)

Total(N=719)293 (40.8)426 (59.2)

Patients with event
Number censored
Probability of being event-free (95% CIa)0.658 (0.605, 0.706) 0.641 (0.586, 0.690) 0.650 (0.612, 0.684)
at 55 weeks
Kaplan-Meier estimates of time to event (weeks)
Quartiles (95% CI)bQ1
40.3 (34.0, 49.0)
42.9 (36.3, 47.9)
41.1 (37.4, 46.0)
Median84.4 (71.7, NE)
77.4 (69.3, 102.1) 83.0 (73.4, 98.7)
Q3
NE
NE
NE
c
Stratified analysis
Comparison versus bevacizumab-EU
Hazard ratiod
0.918
95% CId
0.729, 1.157
2-sided p-valuee
0.4726
A hazard ratio=1 indicated no difference in death between PF-06439535 and bevacizumab-EU;>1 indicated an increase in death in PF-06439535;<1 indicated an increase in death in bevacizumab-EU.
Abbreviations: CI=confidence interval, EU=European Union, ITT=Intent-to-Treat, N=total number of patients,
NE=not evaluable, Q1=25th percentile, Q3=75th percentile.
a. Estimated from the Kaplan-Meier curve; calculated from the product-limit method.
b. Based on the Brookmeyer and Crowley method.
c. Stratified by smoking, sex, and region.
d. Based on the Cox proportional hazards model stratified by smoking, sex, and region.
e. Two-sided p-value from the log-rank test stratified by smoking, sex, and region.

Secondary Pharmacokinetic Endpoints:
Patients received chemotherapy of carboplatin and paclitaxel for at least 4 (unless shorter due
to death, withdrawal of consent, or early termination of the trial) and no more than 6 cycles.
Mean trough (pre-dose) and apparent peak (1 hour post end of infusion) concentrations werecomparable between the 2 treatment groups for all time points measured from Baseline(defined as Hour 0, Cycle 1 Day 1) through Cycle 5 Day 1 (Table 7)

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Table 7.

Summary of Serum Concentration of PF-06439535 and Bevacizumab-EU Versus Time - PK Population

PlannedTime Post
N
NALQ
Mean
SD
CV (%)MedianMinimum
Maximum
Infusion
Start
Concentration Units: ng/mL, Treatment Group: PF-06439535
Cycle 1 Day 1
0h
333
6a
68.08
705.531036
0.00000.000
11300
2 h 30 min
319
309
280000103260372820000.000
546000
Cycle 2 Day 1
0h
310
308
54350
44479
82
49050
0.000
460000
Cycle 3 Day 1
0h
206
206
81090
48671
60
77450
4040
495000
Cycle 4 Day 1
0h
277
277
100900
54979
54
94700
1000
475000
Cycle 5 Day 1
0h
257
256
10530048469
461010000.000
4940001 h 30 min
192
192
3607001311703637250019700
636000Concentration Units: ng/mL, Treatment Group: Bevacizumab-EU
Cycle 1 Day 1
0h
338
7a
116.4
1032.1886
0.00000.000
12300
2 h 30 min
326
32130220010036033
3000000.000
525000
Cycle 2 Day 1
0h
326
324
58930
49452
84
52650
0.000
522000
Cycle 3 Day 1
0h
211
211
83350
32384
39
79700
5270
259000
Cycle 4 Day 1
0h
299
298
99750
50531
51
96500
0.000
697000
Cycle 5 Day 1
0h
271
271
11000065416
591060005610
7230001 h 30 min
201
201
3772001422503838700028700
1010000
Summary statistics were calculated by setting concentration values below the lower limit of quantification (250 ng/mL) to 0.
Samples with a time deviation of >20% or any positive time deviation from the 0 h planned time point were excluded from this table.
Abbreviations: Cmax=maximum concentration, CV=coefficient of variation, EU=European Union, h=hour(s), min=minutes, N=number of observations(non-missing concentrations), NALQ=number of observations above lower limit of quantification (250 ng/mL), PK=pharmacokinetic, SD=standard deviation.
a. Patients with pre-dose concentrations >5% of Cmax on Cycle 1 Day 1 were excluded from this table.

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Visit

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Secondary Immunogenicity Endpoints:
A summary of Baseline and overall post-treatment ADA incidences are presented in Table 8.
One (1, 0.3%) patient in the PF-06439535 group and 3 (0.8%) patients in thebevacizumab-EU group tested positive for ADA (titer 2.29) at Baseline. For the overall
post-treatment assessment, 5 (1.5%) patients in the PF-06439535 group and 5 (1.4%) patientsin the bevacizumab-EU group were reported ADA positive.
Table 8.

Summary of ADA Incidence by Treatment Group - Safety Population

Visit

Criteria

Cycle 1
(prior to treatment)nPositive
Negative
Not testednPositive
Negative

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Overall(post-treatment)

PF-06439535(N=356)352
1 (0.3)350 (99.4)
1 (0.3)339
5 (1.5)334 (98.5)

Bevacizumab-EU(N=358)353
3 (0.8)350 (99.2)
0350
5 (1.4)345 (98.6)

Total(N=714)705
4 (0.6)700 (99.3)
1 (0.1)689
10 (1.5)
679 (98.5)

Percentages were based on the number of patients at each visit. All samples were taken prior to dosing.
For calculation of the overall incidence of post-treatment ADA, n=number of patients with at least 1 post
Cycle 1 ADA sample tested. Patients with a positive ADA sample at any time post Cycle 1 were defined ashaving an overall positive ADA status.
ADA positive sample was defined as ADA titer 2.29, ADA negative sample was defined as ADA titer <2.29.
Abbreviations: ADA=anti-drug antibody, EU=European Union, N=the number of patients who received study
drug, n=the number of patients evaluated at each visit.

All ADA positive samples were tested subsequently in the single NAb assay. A summary of
Baseline and overall post-treatment NAb incidences are presented in Table 9. At Baseline,
1 (PF-06439535 treatment group) out of the 4 patients who tested positive for ADA wasreported positive for NAb (titer 1.70). For the overall post-treatment assessment, of the
5 patients who reported positive ADA status in the PF-06439535 group, none were reported
as NAb positive; of the 5 patients who reported positive ADA status in the bevacizumab-EUgroup, 3 (0.9%) patients reported NAb positive.

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Table 9.

Summary of NAb Incidence by Treatment Group - Safety Population

Visit

Criteria

Cycle 1
(prior to treatment)nPositive
Negative
Not testednPositive
Negative

Overall(post-treatment)

PF-06439535(N=356)352
1 (0.3)0351 (99.7)339
0339 (100.0)

Bevacizumab-EU(N=358)353
03 (0.8)350 (99.2)
350
3 (0.9)347 (99.1)

Total(N=714)705
1 (0.1)3 (0.4)701 (99.4)
689
3 (0.4)686 (99.6)

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Percentages were based on the number of patients at each visit. All samples were taken prior to dosing.
For calculation of the overall incidence of post-treatment NAb, n=number of patients with at least 1 post
Cycle 1 Day 1 ADA sample tested.
Patients with a positive NAb sample at any time post Cycle 1 Day 1 dose were defined as having an overall
positive NAb status; while patients without a NAb positive sample at any cycle post Cycle 1 Day 1 dose were
defined as having an overall negative NAb status.
NAb positive samples were defined as NAb titer 1.70. NAb negative samples were defined as NAb titer<1.70.
Abbreviations: ADA=anti-drug antibody, EU=European Union, N=the number of patients who received study
drug, n=the number of patients evaluated at each visit, NAb=neutralizing antibody.

Safety Results:
All patients who were randomized and received at least 1 dose of study treatment were
included in the safety population. Of the 719 randomized patients, 714 received at least
1 dose of the study treatment (356 patients in the PF-06439535 group and 358 patients in thebevacizumab-EU group). Overall, the mean (SD) duration of treatment for patients in the
PF-06439535 group and the bevacizumab-EU group was 35.2 (27.19) weeks and 34.9 (25.96)
weeks, respectively.
The majority of all patients experienced at least 1 treatment-emergent adverse events (TEAE,
all causalities), with 344 (96.6%) patients in the PF-06439535 group and
347 (96.9%) patients in the bevacizumab-EU group reporting a total of 2442 and2470 TEAEs, respectively. Bevacizumab-related AEs were those AEs related tobevacizumab (with or without causal relationship to chemotherapy) according to theinvestigator’s assessment. Approximately half of all patients experienced at least
1 bevacizumab-related TEAE, with 190 (53.4%) patients in the PF-06439535 group and
199 (55.6%) patients in the bevacizumab-EU group reporting a total of 625 and574 bevacizumab-related TEAEs, respectively.
Serious Adverse Event
Treatment –emergent SAEs are summarized in Table 10 (all causalities) and Table 11(treatment-related). Overall, 81 (22.8%) patients in the PF-06439535 group and80 (22.3%) patients in the bevacizumab-EU group experienced at least 1 SAE (all causalities).
Among them, 23 (6.5%) patients in the PF-06439535 group and 17 (4.7%) patients in thebevacizumab-EU group experienced at least 1 bevacizumab-related SAE. The mostfrequently reported SAEs were pneumonia (8 [2.2%] patients in the PF-06439535 group andTemplate version 1.6

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6 [1.7%] patients in the bevacizumab-EU group), febrile neutropenia (5 [1.4%] patients in the
PF-06439535 group and 7 [2.0%] patients in the bevacizumab-EU group), and neutropenia(4 [1.1%] patients in the PF-06439535 group and 6 [1.7%] patients in the bevacizumab-EUgroup). The most frequently reported bevacizumab-related SAEs were neutropenia, which
was reported by 1 (0.3%) patient in the PF-06439535 group and 3 (0.8%) patients in thebevacizumab-EU group, and pulmonary embolism, which was reported by 2 (0.6%) patientsin the PF-06439535 group and 2 (0.6%) patients in the bevacizumab-EU group.

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Table 10. Treatment-Emergent Serious Adverse Events – All Causality

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Number of Patients Evaluable for AEs
Number (%) of Patients with SAEs by
SOC and
MedDRAa Preferred Term
With any AEs
Blood and Lymphatic System Disorders
Anaemia
Febrile neutropenia
Leukopenia
Neutropenia
Pancytopenia
Thrombocytopenia
Cardiac Disorders
Acute coronary syndrome
Acute myocardial infarction
Angina unstable
Cardiac arrest
Cardiac failure
Cardio-respiratory arrest
Cardiovascular insufficiency
Myocardial infarction
Right ventricular failure
Gastrointestinal Disorders
Abdominal pain
ColitisColitis ischaemic
Constipation
Diarrhoea
Enterocolitis
Faecaloma
Gastritis
Haemorrhoidal haemorrhage
Ileus
Intestinal obstruction
NauseaNeutropenic colitis
Peptic ulcer
Rectal haemorrhage
Small intestinal perforation
Subileus
Vomiting
General Disorders and Administration
Site Conditions
Asthenia
Chest pain
Death
Disease progression
General physical health deterioration
Pain
Hepatobiliary Disorders
Cholangitis acutePF-06439535(N = 356)n (%)

Bevacizumab-EU(N = 358)
n (%)

Total
(N = 714)n (%)

81 (22.8)
12 (3.4)
2 (0.6)5 (1.4)2 (0.6)4 (1.1)1 (0.3)3 (0.8)7 (2.0)1 (0.3)1 (0.3)1 (0.3)1 (0.3)1 (0.3)0
1 (0.3)1 (0.3)08 (2.2)00
1 (0.3)0
2 (0.6)
1 (0.3)0
1 (0.3)1 (0.3)00
00
1 (0.3)000
1 (0.3)80 (22.3)
18 (5.0)5 (1.4)7 (2.0)06 (1.7)1 (0.3)3 (0.8)8 (2.2)1 (0.3)1 (0.3)0
1 (0.3)0
2 (0.6)
1 (0.3)1 (0.3)1 (0.3)14 (3.9)
1 (0.3)1 (0.3)0
2 (0.6)2 (0.6)0
1 (0.3)00
1 (0.3)1 (0.3)2 (0.6)
1 (0.3)0
1 (0.3)1 (0.3)1 (0.3)1 (0.3)161 (22.5)
30 (4.2)
7 (1.0)12 (1.7)
2 (0.3)10 (1.4)
2 (0.3)6 (0.8)15 (2.1)
2 (0.3)2 (0.3)1 (0.1)2 (0.3)1 (0.1)2 (0.3)2 (0.3)2 (0.3)1 (0.1)22 (3.1)
1 (0.1)1 (0.1)1 (0.1)2 (0.3)4 (0.6)
1 (0.1)1 (0.1)1 (0.1)1 (0.1)1 (0.1)1 (0.1)2 (0.3)1 (0.1)1 (0.1)1 (0.1)1 (0.1)1 (0.1)2 (0.3)

12 (3.4)

11 (3.1)

23 (3.2)

4 (1.1)1 (0.3)2 (0.6)4 (1.1)1 (0.3)2 (0.6)3 (0.8)2 (0.6)

1 (0.3)1 (0.3)3 (0.8)5 (1.4)0
1 (0.3)00

5 (0.7)2 (0.3)5 (0.7)9 (1.3)1 (0.1)3 (0.4)3 (0.4)2 (0.3)

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Table 10. Treatment-Emergent Serious Adverse Events – All Causality (Continued)
Page 2 of 3
Number (%) of Patients with SAEs by
SOC and
MedDRAa Preferred Term
Cholelithiasis
Immune System Disorders
Anaphylactic reaction
Infections and Infestations
Anal infection
Appendictis perforated
Bacteraemia
Disseminated tuberculosis
Enterocolitis infectious
Febrile infection
Gastroenteritis
Infection
Infectious pleural effusion
Lower respiratory tract infection
Lung abscessLung infection
Oral fungal infection
Pleural infection
Pneumonia
Respiratory tract infection
Sepsis
Septic shock
Sinusitis
Soft tissue infection
Urinary tract infection
Injury, Poisoning and Procedural
Complications
Femur fracture
Fracture
Infusion related reaction
Subarachnoid haemorrhage
Investigations
Alanine aminotransferase increased
Blood bilirubin increased
Neutrophil count decreased
Metabolism and Nutrition Disorders
Decreased appetite
Dehydration
Hypercalcaemia
Hyperkalaemia
Hyponatraemia
Musculoskeletal and Connective Tissue
Disorders
Bone pain
Myalgia
Neoplasms Benign, Malignant andUnspecified (Including Cysts and Polyps)
Bone cancer metastatic
Neoplasm progression

PF-06439535

Bevacizumab-EU

Total

1 (0.3)00
18 (5.1)
1 (0.3)0
1 (0.3)00
1 (0.3)4 (1.1)00
1 (0.3)0
1 (0.3)00
8 (2.2)2 (0.6)00
1 (0.3)0
1 (0.3)0
1 (0.3)1 (0.3)19 (5.3)
01 (0.3)0
1 (0.3)1 (0.3)00
1 (0.3)1 (0.3)2 (0.6)
1 (0.3)1 (0.3)1 (0.3)1 (0.3)6 (1.7)02 (0.6)
1 (0.3)0
1 (0.3)2 (0.6)

1 (0.1)1 (0.1)1 (0.1)37 (5.2)
1 (0.1)1 (0.1)1 (0.1)1 (0.1)1 (0.1)1 (0.1)4 (0.6)
1 (0.1)1 (0.1)3 (0.4)1 (0.1)2 (0.3)1 (0.1)1 (0.1)14 (2.0)
2 (0.3)2 (0.3)1 (0.1)1 (0.1)1 (0.1)3 (0.4)1 (0.3)3 (0.8)4 (0.6)

1 (0.3)000
2 (0.6)
1 (0.3)1 (0.3)1 (0.3)5 (1.4)00
1 (0.3)0
4 (1.1)0
1 (0.3)1 (0.3)1 (0.3)1 (0.3)00
1 (0.3)2 (0.6)
1 (0.3)1 (0.3)0
1 (0.3)0

1 (0.1)1 (0.1)1 (0.1)1 (0.1)3 (0.4)1 (0.1)1 (0.1)2 (0.3)7 (1.0)1 (0.1)1 (0.1)1 (0.1)1 (0.1)4 (0.6)0

3 (0.8)3 (0.4)00

2 (0.6)
1 (0.3)2 (0.3)1 (0.1)2 (0.6)4 (1.1)6 (0.8)02 (0.6)

1 (0.3)2 (0.6)

1 (0.1)4 (0.6)

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Table 10. Treatment-Emergent Serious Adverse Events – All Causality (Continued)
Page 3 of 3
Number (%) of Patients with SAEs by
PF-06439535
Bevacizumab-EU
Total
SOC and
MedDRAa Preferred Term
Tumor necrosis01 (0.3)1 (0.1)
Nervous System Disorders
5 (1.4)5 (1.4)10 (1.4)
Cerebral haemorrhage
1 (0.3)0
1 (0.1)
Cerebral ischaemia
1 (0.3)0
1 (0.1)
Dizziness01 (0.3)1 (0.1)
Haemorrhagic stroke
1 (0.3)0
1 (0.1)Headache
1 (0.3)0
1 (0.1)Ischaemic stroke03 (0.8)3 (0.4)
Mononeuropathy
01 (0.3)1 (0.1)Paraesthesia
1 (0.3)0
1 (0.1)
Renal and Urinary Disorders
2 (0.6)
1 (0.3)3 (0.4)
Proteinuria
1 (0.3)0
1 (0.1)
Renal cyst
1 (0.3)0
1 (0.1)
Urinary retention0
1 (0.3)1 (0.1)
Respiratory, Thoracic and Mediastinal
19 (5.3)
14 (3.9)33 (4.6)
Disorders
Acute respiratory failure01 (0.3)1 (0.1)Chronic obstructive pulmonary disease01 (0.3)1 (0.1)Cough0
1 (0.3)1 (0.1)
Dyspnoea
2 (0.6)2 (0.6)4 (0.6)
Epistaxis
2 (0.6)
1 (0.3)3 (0.4)
Haemoptysis
2 (0.6)2 (0.6)4 (0.6)
Pneumonitis
1 (0.3)0
1 (0.1)
Pneumothorax
2 (0.6)
1 (0.3)3 (0.4)
Pulmonary embolism
7 (2.0)2 (0.6)9 (1.3)Pulmonary haemorrhage
3 (0.8)3 (0.8)6 (0.8)
Pulmonary oedema
01 (0.3)1 (0.1)
Respiratory failure
1 (0.3)0
1 (0.1)
Vascular Disorders
5 (1.4)3 (0.8)8 (1.1)
Brachiocephalic vein thrombosis
1 (0.3)0
1 (0.1)
Embolism arterial
1 (0.3)1 (0.3)2 (0.3)
Haemorrhage
1 (0.3)0
1 (0.1)Hypertensive crisis
01 (0.3)1 (0.1)Ischaemia
1 (0.3)0
1 (0.1)
Shock haemorrhagic01 (0.3)1 (0.1)
Subgaleal haematoma
1 (0.3)0
1 (0.1)Abbreviations: AE=adverse event, EU=European Union, MedDRA=Medical Dictionary for Regulatory
Activities, SAE=serious adverse event, SOC=system organ class.
a. MedDRA version 20.1 coding dictionary applied.

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Table 11. Treatment-Emergent Serious Adverse Events – Bevacizumab-Relateda

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Page 1 of 2
Number (%) of Patients

PF-06439535(N = 356)

Bevacizumab-EU(N = 358)

Total(N = 714)

Number (%) of Patients with SAEs by
SOC and
MedDRAb Preferred Term
With any AEs
Blood and Lymphatic System Disorders
Anaemia
Febrile neutropenia
Leukopenia
Neutropenia
Thrombocytopenia
Cardiac Disorders
Acute myocardial infarction
Gastrointestinal Disorders
Abdominal pain
Colitis ischaemic
Gastritis
Small intestinal perforation
Vomiting
General Disorders and Administration Site Conditions
Asthenia
Death
Infections and Infestations
Appendictis perforated
Enterocolitis infectious
Pleural infection
Pneumonia
SepsisUrinary tract infection
Investigations
Neutrophil count decreased
Metabolism and Nutrition Disorders
Decreased appetite
Dehydration
Hyponatraemia
Nervous System Disorders
Cerebral haemorrhage
Renal and Urinary Disorders
Proteinuria
Respiratory, Thoracic and Mediastinal Disorders
Cough
Dyspnoea
Epistaxis
Haemoptysis
Pulmonary embolism
Pulmonary haemorrhage
Vascular Disorders
Brachiocephalic vein thrombosis
Embolism arterial
Haemorrhage

23 (6.5)5 (1.4)2 (0.6)2 (0.6)
1 (0.3)1 (0.3)1 (0.3)1 (0.3)1 (0.3)3 (0.8)0
1 (0.3)1 (0.3)0
1 (0.3)3 (0.8)2 (0.6)
1 (0.3)3 (0.8)000
2 (0.6)0
1 (0.3)1 (0.3)1 (0.3)2 (0.6)00
2 (0.6)
1 (0.3)1 (0.3)1 (0.3)1 (0.3)7 (2.0)01 (0.3)2 (0.6)2 (0.6)2 (0.6)
1 (0.3)2 (0.6)
1 (0.3)0
1 (0.3)17 (4.7)
7 (2.0)1 (0.3)1 (0.3)0
3 (0.8)2 (0.6)00
2 (0.6)
1 (0.3)00
1 (0.3)0000
3 (0.8)1 (0.3)1 (0.3)1 (0.3)0
1 (0.3)000
1 (0.3)1 (0.3)1 (0.3)00
000
5 (1.4)1 (0.3)0
1 (0.3)0
2 (0.6)
1 (0.3)1 (0.3)0
1 (0.3)040 (5.6)
12 (1.7)
3 (0.4)3 (0.4)1 (0.1)4 (0.6)3 (0.4)1 (0.1)1 (0.1)5 (0.7)1 (0.1)1 (0.1)1 (0.1)1 (0.1)1 (0.1)3 (0.4)2 (0.3)1 (0.1)6 (0.8)1 (0.1)1 (0.1)1 (0.1)2 (0.3)1 (0.1)1 (0.1)1 (0.1)1 (0.1)3 (0.4)1 (0.1)1 (0.1)2 (0.3)1 (0.1)1 (0.1)1 (0.1)1 (0.1)
12 (1.7)
1 (0.1)1 (0.1)3 (0.4)2 (0.3)4 (0.6)2 (0.3)3 (0.4)1 (0.1)1 (0.1)1 (0.1)

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Table 11. Treatment-Emergent Serious Adverse Events – Bevacizumab-Relateda(Continued)
Page 2 of 2
Abbreviations: AE=adverse event, EU=European Union, MedDRA=Medical Dictionary for Regulatory
Activities, SAE=serious adverse event, SOC=system organ class.
a. AEs related to bevacizumab with or without causal relationship to chemotherapy.
b. MedDRA version 20.1 coding dictionary applied.

Non-Serious Adverse Events:

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Treatment-emergent non-serious AEs in 5% of patients are summarized in Table 12 (allcausality) and Table 13 (bevacizumab-related). The most frequently reported non-serious
AEs were alopecia (166 [46.6%] patients in the PF-06439535 group and
165 [46.1%] patients in the bevacizumab-EU group), and anaemia (102 [28.7%] patients in
the PF-06439535 group and 106 [29.6%] patients in the bevacizumab-EU group). The mostfrequently reported bevacizumab-related non-serious AEs were hypertension(45 [12.6%] patients in the PF-06439535 group and 40 [11.2%] patients in thebevacizumab-EU group), and anaemia (28 [7.9%] patients in the PF-06439535 group and30 [8.4%] patients in the bevacizumab-EU group).

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Table 12. Treatment-Emergent Non-Serious Adverse Events in 5% of Patients of
Any Treatment Group – All Causality

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Page 1 of 2
Number (%) of Patients
Number (%) of Patients with AEs by
SOC and
MedDRAa Preferred Term
With any AEs
Blood and Lymphatic System Disorders
Anaemia
Leukopenia
Neutropenia
Thrombocytopenia
Gastrointestinal Disorders
Constipation
Diarrhoea
NauseaVomiting
General Disorders and Administration
Site Conditions
Asthenia
FatiguePyrexia
Injury, Poisoning and Procedural
Complications
Infusion related reaction
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood alkaline phosphatase increased
Blood creatinine increased
Platelet count decreased
Weight decreased
Metabolism and Nutrition Disorders
Decreased appetite
Musculoskeletal and Connective Tissue
Disorders
Arthralgia
Bone pain
Myalgia
Pain in extremity
Nervous System Disorders
Headache
Neuropathy peripheral
Paraesthesia
Peripheral sensory neuropathy
Polyneuropathy
Renal and Urinary Disorders
Proteinuria
Respiratory, Thoracic and Mediastinal
DisordersCough
Dyspnoea

PF-06439535(N = 356)

Bevacizumab-EU(N = 358)

Total(N = 714)

328 (92.1)
153 (43.0)
102 (28.7)
26 (7.3)
59 (16.6)55 (15.4)
128 (36.0)
39 (11.0)
46 (12.9)
71 (19.9)41 (11.5)333 (93.0)
166 (46.4)
106 (29.6)
30 (8.4)
66 (18.4)
66 (18.4)
126 (35.2)
27 (7.5)
48 (13.4)
69 (19.3)
33 (9.2)

661 (92.6)
319 (44.7)
208 (29.1)
56 (7.8)
125 (17.5)
121 (16.9)
254 (35.6)
66 (9.2)
94 (13.2)
140 (19.6)
74 (10.4)

126 (35.4)

124 (34.6)

250 (35.0)

46 (12.9)
73 (20.5)
24 (6.7)

43 (12.0)
71 (19.8)
23 (6.4)

89 (12.5)
144 (20.2)
47 (6.6)

19 (5.3)

22 (6.1)

41 (5.7)

19 (5.3)
116 (32.6)
49 (13.8)
44 (12.4)
29 (8.1)
16 (4.5)
23 (6.5)
36 (10.1)
48 (13.5)
48 (13.5)

22 (6.1)
107 (29.9)
39 (10.9)
37 (10.3)
32 (8.9)21 (5.9)19 (5.3)
29 (8.1)
46 (12.8)
46 (12.8)

41 (5.7)
223 (31.2)
88 (12.3)
81 (11.3)
61 (8.5)
37 (5.2)
42 (5.9)65 (9.1)
94 (13.2)
94 (13.2)

110 (30.9)

115 (32.1)

225 (31.5)

40 (11.2)
25 (7.0)
54 (15.2)
16 (4.5)
156 (43.8)
30 (8.4)
53 (14.9)40 (11.2)
34 (9.6)
23 (6.5)
28 (7.9)
28 (7.9)43 (12.0)
23 (6.4)
49 (13.7)
23 (6.4)
172 (48.0)
37 (10.3)
65 (18.2)
31 (8.7)
46 (12.8)
19 (5.3)
34 (9.5)
34 (9.5)

83 (11.6)
48 (6.7)
103 (14.4)
39 (5.5)328 (45.9)
67 (9.4)
118 (16.5)
71 (9.9)80 (11.2)
42 (5.9)
62 (8.7)
62 (8.7)

86 (24.2)

94 (26.3)

180 (25.2)

41 (11.5)
32 (9.0)47 (13.1)
35 (9.8)

88 (12.3)
67 (9.4)

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Table 12. Treatment-Emergent Non-Serious Adverse Events in 5% of Patients of
Any Treatment Group – All Causality (Continued)
Page 2 of 2
Number (%) of Patients with AEs by
PF-06439535
Bevacizumab-EU
Total
SOC and
MedDRAa Preferred Term
Epistaxis
40 (11.2)
32 (8.9)72 (10.1)
Skin and Subcutaneous Tissue Disorders
171 (48.0)
173 (48.3)
344 (48.2)
Alopecia
166 (46.6)
165 (46.1)
331 (46.4)
Rash
9 (2.5)21 (5.9)30 (4.2)
Vascular Disorders
60 (16.9)
62 (17.3)
122 (17.1)
Hypertension
60 (16.9)
62 (17.3)
122 (17.1)
Abbreviations: AE=adverse event, EU=European Union, MedDRA=Medical Dictionary for Regulatory
Activities, SOC=system organ class.
a. MedDRA version 20.1 coding dictionary applied.

Table 13. Treatment-Emergent Non-Serious Adverse Events in 5% of Patients of
Any Treatment Group – Bevacizumab-Relateda
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Number (%) of Patients

PF-06439535(N = 356)

Bevacizumab-EU(N = 358)

Total(N = 714)

Number (%) of Patients with AEs by
SOC and
MedDRAb Preferred Term
With any AEs
127 (35.7)
125 (34.9)
252 (35.3)
Blood and Lymphatic System Disorders
38 (10.7)
44 (12.3)
82 (11.5)
Anaemia28 (7.9)30 (8.4)
58 (8.1)
Neutropenia
15 (4.2)
19 (5.3)
34 (4.8)
General Disorders and Administration
31 (8.7)
23 (6.4)
54 (7.6)
Site Conditions
Fatigue
31 (8.7)
23 (6.4)
54 (7.6)
Investigations
18 (5.1)
14 (3.9)32 (4.5)
Alanine aminotransferase increased
18 (5.1)
14 (3.9)32 (4.5)
Renal and Urinary Disorders
21 (5.9)27 (7.5)
48 (6.7)
Proteinuria
21 (5.9)27 (7.5)
48 (6.7)
Respiratory, Thoracic and Mediastinal
30 (8.4)
26 (7.3)
56 (7.8)
Disorders
Epistaxis
30 (8.4)
26 (7.3)
56 (7.8)
Vascular Disorders
45 (12.6)
40 (11.2)
85 (11.9)
Hypertension
45 (12.6)
40 (11.2)
85 (11.9)
Abbreviations: AE=adverse event, EU=European Union, MedDRA=Medical Dictionary for Regulatory
Activities, SOC=system organ class.
a. AEs related to bevacizumab with or without causal relationship to chemotherapy.
b. MedDRA version 20.1 coding dictionary applied.

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Withdrawals Due to AEs:
There were 85 (23.9%) patients in the PF-06439535 group and 86 (24.0%) patients in thebevacizumab-EU group who were permanently discontinued from any treatment(ie, discontinued from bevacizumab and/or paclitaxel and/or carboplatin) due to AEs. The
most frequently reported AE that led to permanent discontinuation from any treatment waspolyneuropathy (8 [2.2%] patients in the PF-06439535 group and 5 [1.4%] patients in thebevacizumab-EU group). There were 33 (9.3%) patients in the PF-06439535 group and25 (7.0%) patients in the bevacizumab-EU group who were permanently discontinued fromany treatment (ie, discontinued from bevacizumab and/or paclitaxel and/or carboplatin) due
to bevacizumab-related AEs. The most frequently reported bevacizumab-related AE that led
to permanent discontinuation from any treatment was proteinuria (5 [1.4%] patients in the
PF-06439535 group and 2 [0.6%] patients in the bevacizumab-EU group).

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Death:
Deaths occurring during the safety reporting period (during the treatment period and up to
28 days after the last dose or the start of subsequent anti-cancer therapy [whichever was
earlier]) are presented as Grade 5 TEAEs. In the PF-06439535 group, out of 356 patients
who received study treatment, there were 21 (5.9%) patients with Grade 5 TEAEs within thesafety reporting period. In the bevacizumab-EU group, out of 358 patients who received
study treatment, there were 24 (6.7%) patients with Grade 5 TEAEs within the safety
reporting period. There was 1 bevacizumab-related Grade 5 event (pulmonary hemorrhage)in the bevacizumab-EU group and 6 bevacizumab-related Grade 5 events (acute myocardial
infarction, pneumonia, hemoptysis, pulmonary hemorrhage, hemorrhage, and death) in the
PF-06439535 group. The events of acute myocardial infarction, pneumonia and pulmonary
hemorrhage in the PF-06439535 group were also related to paclitaxel and carboplatin.
Bevacizumab-related fatal events were consistent with the complications of underlying
disease and known safety profile of Avastin. Overall, the incidence of Grade 5 events (allcause deaths) was similar between the 2 treatment groups.
Severity of Adverse Events
In total, there were 343 (48.0%) patients (171 [48.0%] patients in the PF-06439535 groupand 172 [48.0%] patients in the bevacizumab-EU group) with a TEAE reported at Grade 3 orhigher, with a comparable incidence between the 2 treatment groups. The most frequently
reported Grade 3 or higher TEAEs were hypertension (33 [9.3%] patients in the
PF-06439535 group and 31 [8.7%] patients in the bevacizumab-EU group), followed byneutropenia (26 [7.3%] patients in the PF-06439535 group and 32 [8.9%] patients in thebevacizumab-EU group), and anemia (19 [5.3%] patients in the PF-06439535 group and18 [5.0%] patients in the bevacizumab-EU group).
In the PF-06439535 group, there were 53 (14.9%) patients, 5 (1.4%) patients, and
6 (1.7%) patients who had bevacizumab-related TEAEs with maximum CTCAE Grade 3,
Grade 4, and Grade 5, respectively. In the bevacizumab-EU group, the corresponding
numbers of patients were 35 (9.8%), 14 (3.9%), and 1 (0.3%), respectively. The mostfrequently reported Grade 3 and Grade 4 bevacizumab-related TEAEs were hypertension,

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Protocol B7391003 – 15 November 2018 – Finalwith 23 (6.5%) patients (Grade 3: 23) in the PF-06439535 group, and 14 (3.9%) patients(Grade 3: 14) in the bevacizumab-EU group followed by neutropenia with 6 (1.7%) patients(Grade 3: 4 [1.1%]; Grade 4: 2 [0.6%]) in the PF-06439535 group and 8 (2.2%) patients(Grade 3: 2 [0.6%]; Grade 4: 6 [1.7%]) in the bevacizumab-EU group) and anemia, with 5(1.4%) patients (Grade 3: 5) in the PF-06439535 group and 4 (1.1%) patients (Grade 3: 4) inthe bevacizumab-EU group.
Clinical Laboratory Abnormalities
The number and percentage of patients with laboratory abnormalities were 303 (88.6%) in
the PF-06439535 group and 304 (87.4%) in the bevacizumab-EU group, respectively.
Four (4) patients (2 in the PF-06439535 group, and 2 in the bevacizumab-EU group) had
elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) defined as3 × upper limit of normal (ULN) and elevated total bilirubin of 2 × ULN which wereconsidered as clinically significant.

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CONCLUSIONS:Study B7391003 met its primary objective, based on the analysis of the primary efficacy
endpoint ORR in patients who received PF-06439535 in combination with paclitaxel andcarboplatin versus those who received bevacizumab-EU in combination with paclitaxel
and carboplatin in first-line treatment of advanced (unresectable, locally advanced,
recurrent or metastatic) non-squamous NSCLC.



Similarity between PF-06439535 and bevacizumab-EU was statistically demonstrated forthe primary efficacy endpoint, ORR (defined as the percent of patients within eachtreatment group that achieved CR or PR by Week 19 and subsequently confirmed ona follow-up tumor assessment by Week 25) based on the pre-specified equivalence
margins required by US FDA, EU EMA and Japan PMDA.



Sensitivity analyses for ORR using stratification factors, and sensitivity analyses using
the PP population supported the results of the primary endpoint analysis.

No statistically significant or clinically meaningful differences between the 2 treatmentgroups were observed for the secondary efficacy endpoints, which included DOR, 1-year
PFS rate, and 1-year survival rate.

Both treatments showed comparable safety profiles. No clinically meaningful safety
differences were identified between the 2 treatment groups. No new safety signal was
identified.

Trough and apparent peak serum bevacizumab concentrations were comparable for both
treatments.



The observed rate of ADA and NAb was low, with comparable percentages of patientswith ADA and NAb observed for the 2 treatment groups. Given the low number ofpatients with ADA, the association between immunogenicity and safety could not be
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Public Disclosure Synopsis
Protocol B7391003 – 15 November 2018 – Final

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evaluated. The patients with ADA did not experience serious IRRs or anaphylactic
reactions.

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