Final Clinical Study Report
Protocol B7971001

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc
Investigational Product: PF-06747775
Clinical Study Report Synopsis: Protocol B7971001
Protocol Title: Phase 1/2 Open-Label Study of PF-06747775 (Epidermal Growth Factor
Receptor T790M Inhibitor) in Patients With Advanced Epidermal Growth Factor Receptor
Mutant (Del 19 or L858R ±T790M) Non-Small Cell Lung 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: 14 May 2015
Study Completion Date: 28 May 2020 (This study was terminated prematurely.)
Report Date: 19 October 2020
Previous Report Date(s): Not Applicable
Phase of Development: Phase 1/2
Primary and Secondary Study Objectives and Endpoints:
The objectives and endpoints are presented in Table S1, Table S2 and Table S3.

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Final Clinical Study Report
Protocol B7971001

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints - Phase 1TypePrimary
SafetySecondary
SafetyObjective

Endpoint

To evaluate safety and tolerability at increasing
dose levels of PF-06747775 as a single agent inorder to estimate the maximum tolerated dose(MTD) and recommended Phase 2 dose (RP2D)
in patients with advanced epidermal growth
factor receptor mutant (EGFRm) non-small celllung cancer (NSCLC) (exon deletion 19 orexon 21 L858R substitution, with or without
T790M) following ≥1 prior line of therapy,
which must have included an approved
epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitor (TKI)•Cycle 1 dose limiting toxicities(DLTs)

To evaluate the overall safety profile of
PF-06747775•Overall safety profile of
PF-06747775 characterized bytype, incidence, severity,seriousness, and relationship tostudy therapy of adverse events(AEs)
Laboratory test abnormalities•

Pharmacokinetics(PK)

To characterize the effects of single-agent
PF-06747775 on corrected QT (QTc)•QTc for heart rate using
Fridericia’s formula (QTcF) andQTc for heart rate using Bazett'sformula (QTcB)

To characterize single dose and steady state PK
profiles of single-agent PF-06747775•Plasma area under the plasma
concentration-time profile fromtime 0 extrapolated to infinite
time (AUCinf), maximum
observed plasma concentration(Cmax), terminal plasma half-life(t½), apparent oral clearance(CL/F), and apparent volume ofdistribution (Vz/F) ofPF-06747775 after single dose
Pre-dose concentration (Ctrough),area under the curve at steadystate (AUCtau), CL/F, observed
accumulation ratio for AUCtau(Rac), and steady state
accumulation ratio (Rss) ofPF-06747775 after multipledoses•PFIZER CONFIDENTIAL
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Protocol B7971001

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints - Phase 1
Type

Objective
To evaluate the effect of PF-06747775 at steadystate on the exposure of a single dose ofsildenafil, a cytochrome P450 3A4 (CYP3A4)
probe•Endpoint
Plasma AUCinf, Cmax, and CL/Fof sildenafil alone and incombination with steady state
plasma concentrations of
PF-06747775

To characterize the effect of food on theexposure of PF-06747775 at the RP2D

•Plasma AUCtau and Cmax of
PF-06747775 at the RP2D under
fed and fasted conditions

To characterize the effect of esomeprazole, aproton pump inhibitor (PPI), on the exposure of
PF-06747775 at the RP2D

•Plasma AUCtau and Cmax of
PF-06747775 at the RP2D alone
and in combination withesomeprazole treatment

To characterize the effect of itraconazole, astrong CYP3A4 inhibitor, on the exposure ofPF-06747775 at the RP2D•

Plasma AUCtau and Cmax of
PF-06747775 at the RP2D alone
and in combination withitraconazole treatment

To characterize the effect of rifampin, a strong
CYP3A4 inducer, on the exposure of
PF-06747775 at the RP2D•

Plasma AUCtau and Cmax of
PF-06747775 at the RP2D alone
and in combination withrifampin treatment

Pharmacodynamics(PD)

To assess in tumor and plasma thepresence/absence of EGFR mutations•EGFR mutations in tumor andplasmaEfficacy

To evaluate the anti-tumor activity ofPF-06747775 in both T790M-positive andT790M-negative NSCLC tumors•

Confirmed objective response(OR), per Response Evaluation
Criteria in Solid Tumor(RECIST) version 1.1 for thosepatients with measurable disease

To assess tumor and blood-based biomarkers ofsensitivity and/or resistance to PF-06747775•Tumor and plasma biomarkers
of sensitivity and resistance

ExploratoryPD

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Protocol B7971001

CLINICAL STUDY REPORT SYNOPSIS
Table S2. Study Objectives and Endpoints - Phase 1b/2TypePrimary
Efficacy

SafetySecondary
Efficacy

SafetyObjective

Endpoint

To assess the anti-tumor activity (objectiveresponse rate [ORR]) of single-agent
PF-06747775 in patients with EGFRm
NSCLC (exon deletion 19 or exon 21
L858R substitution, with or without
T790M) (Cohort 1)•Confirmed OR, per RECIST
version 1.1

To assess the progression-free survival(PFS) of PF-06747775 plus palbociclib
versus single-agent PF-06747775 in patientswith EGFRm NSCLC with a secondary
T790M mutation (exon deletion 19 andT790M or exon 21 L858R substitution andT790M) (Cohort 2B)•PFS

To evaluate safety and tolerability anddetermine the RP2D of PF-06747775 plus
palbociclib in patients with EGFRm
NSCLC with a secondary T790M mutation(exon deletion 19 and T790M or exon 21L858R substitution and T790M)(Cohort 2A).

•Cycles 1 and 2 DLTs

To evaluate safety and tolerability andestablish the RP2D of PF-06747775 plus
avelumab in patients with EGFRm NSCLC
with a secondary T790M mutation (exondeletion 19 and T790M or exon 21 L858R
substitution and T790M) (Cohort 3)•Cycle 1 DLTs

To assess duration of objective response(DOR) and overall survival (OS) probabilityat 24 months (all cohorts)••

DOR (all cohorts)
OS probability at 24 months (allcohorts)

To assess ORR (Cohorts 2A, 2B, 3)•

ORR (Cohorts 2A, 2B, 3)

To assess PFS (Cohorts 1, 2A, and 3)•PFS (Cohorts 1, 2A, 3)

To further characterize the AE profile ofPF-06747775 when given as a single agent(Cohorts 1 and 2B) and in combination withpalbociclib (Cohorts 2A and 2B) andavelumab (Cohort 3)•Overall safety profile characterizedby type, incidence, severity,seriousness, and relationship to study
therapy of AEs (all cohorts)
Laboratory test abnormalities (allcohorts)

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Final Clinical Study Report
Protocol B7971001

CLINICAL STUDY REPORT SYNOPSIS
Table S2. Study Objectives and Endpoints - Phase 1b/2
TypeObjective
To further explore the effects ofPF-06747775 on QTc when given as asingle agent (Cohorts 1 and 2B) and incombination with palbociclib (Cohorts 2Aand 2B) and avelumab (Cohort 3)•Endpoint
QTcF and QTcB

To further characterize PF-06747775 PK
when given as a single agent (Cohorts 1 and2B) and in combination with palbociclib(Cohorts 2A and 2B) and avelumab(Cohort 3)•

PK parameters of PF-06747775 asdata permitted

To characterize the PK of palbociclib in
combination with PF-06747775(Cohorts 2A and 2B)•PK parameters of palbociclib, as data
permitted

To characterize the PK of avelumab in
combination with PF-06747775 (Cohort 3)•PK parameters of avelumab, as data
permittedPD

To assess in tumor and plasma thepresence/absence of EGFR mutations (allcohorts)•EGFR mutations in tumor andplasma (all cohorts)

Immunogenicity

To assess the immunogenicity of avelumab
when given in combination withPF-06747775 (Cohort 3)•Avelumab serum anti-drug antibody(ADA) (neutralizing antibody [Nab])(Cohort 3)

To explore the antitumor effect of avelumab
in combination with PF-06747775(Cohort 3) by immune-related Response
Evaluation Criteria in Solid Tumors(irRECIST)••

immune-related best overall response(irBOR)
immune-related progressive disease(irPD)To assess the presence and relative
concentration of PF-06747775 in cerebral
spinal fluid (CSF), as data permitted (allcohorts)•PF-06747775 concentrations in CSF

PK

Exploratory
EfficacyPK

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CLINICAL STUDY REPORT SYNOPSIS
Table S2. Study Objectives and Endpoints - Phase 1b/2TypePD

ObjectiveTo explore the predictive and PDcharacteristics of tumor tissue, peripheral
blood, and urine biomarkers that may berelevant to mechanism of action orresistance to PF-06747775 (all cohorts)••

Tumor tissue, peripheral blood andurine biomarkers including
circulating lymphocytes,
deoxyribonucleic acid (DNA),ribonucleic acid (RNA), and proteinsthat may be related to response ordisease progression on treatment with
PF-06747775 and palbociclib(Cohorts 2A and 2B)•Tumor tissue and peripheral bloodbiomarkers such as PD-L1
expression and tumor- infiltratingcluster of differentiation (CD)8+
T-lymphocytes; T, B, and naturalkiller (NK) cells; effector andmemory T cells; cytokines; T cell
receptor sequences; and expressionof genes related to immune response
and inflammation

To assess tumor and blood-based
biomarkers of sensitivity and/or resistanceto PF-06747775 (all cohorts)

To evaluate the PD effect of PF-06747775
and avelumab on immune parameters inperipheral blood including lymphocyte
subpopulations, serum biomarkers and gene
expression (Cohort 3)

Endpoint
Tumor tissue, peripheral blood, andurine biomarkers of action
mechanism or resistance toPF-06747775 (all cohorts)

To evaluate candidate immune-related
predictive biomarkers of sensitivity orinsensitivity to treatment with avelumab in
combination with PF-06747775 in
pre-treatment tumor samples (eg,programmed death ligand-1 [PD-L1]
expression) (Cohort 3)

Table S3. Study Objectives and Endpoints-Japanese Patients
TypeSafety

Objective
To evaluate the safety and tolerability ofPF-06747775 in Japanese patients (RP2Dtolerability cohort)

••

•
PK

To characterize single dose and steady state
PK profiles of single-agent PF-06747775 inJapanese patients (RP2D tolerability cohortand PK cohort)

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Endpoint
Cycle 1 DLTs
Overall safety profile ofPF-06747775 characterized by type,
incidence, severity, seriousness, andrelationship to study therapy of AEs
Laboratory test abnormalities
PK parameters of PF-06747775
following single and multiple doses
as data permitted

Final Clinical Study Report
Protocol B7971001

CLINICAL STUDY REPORT SYNOPSISMETHODS
Study Design: This was a Phase 1/2 study of PF-06747775 as a single agent and incombination with palbociclib and avelumab in patients with advanced epidermal growth
factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC). The overall clinicalstudy consisted of a Phase 1 single-agent, dose-escalation and Phase 1b/2 dose-expansion
part to determine the single-agent recommended Phase 2 dose (RP2D) of PF-06747775 inpatients with previously-treated EGFRm NSCLC followed by sequential evaluations ofPF-06747775 at the RP2D in 3 different clinical scenarios. Phase 1 was also planned toinclude a series of pharmacokinetic (PK) sub-studies. In addition, this study also included aJapanese patient lead-in cohort (LIC) to evaluate the safety, tolerability and PK ofPF-06747775 as a single agent in Japanese patients with advanced EGFRm NSCLC. This
Japanese LIC was planned to consist of 2 cohorts: RP2D tolerability cohort and PK cohort.
Due to early study termination, enrollment into the food effect and rifampin drug-druginteraction (DDI) PK sub-study, Cohort 2B and Cohort 3 were not initiated. Most
PD/biomarker analyses were also not completed.
Diagnosis and Main Criteria for Inclusion: Patients with evidence of histologically or
cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (exondeletion 19 or exon 21 L858R substitution) NSCLC were enrolled in this study. In Japanesepatients-only LIC, locally advanced or metastatic EGFRm NSCLC patients who progressedon or were intolerant to standard therapy, for which no standard therapy was available or who
declined standard therapy were included in this study.
RESULTSSubject Disposition and Demography:
A total of 65 patients were assigned and treated in this study:•26 patients were treated in the dose escalation part (PF-06747775 doses: 25 mg to600 mg once daily [QD]);•

29 patients were treated with PF-06747775 200 mg QD, a combined group ofPF-06747775 200 mg QD plus sildenafil 25 mg, PF-06747775 200 mg QD plus
esomeprazole/itraconazole, Japan LIC and Cohort 1;•5 patients were treated with PF-06747775 300 mg QD plus sildenafil 25 mg;•5 patents were treated with PF-06747775 200 mg QD plus palbociclib 100 mg QD(Cohort 2A).

All 65 patients permanently discontinued from the study treatment. Thirty-five (53.8%)
patients completed the study and 30 (46.2%) patients permanently discontinued from thestudy.

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Final Clinical Study Report
Protocol B7971001

CLINICAL STUDY REPORT SYNOPSIS
Twenty-five male and 40 female patients were assigned and treated in this study, with themean (standard deviation) age of 60.8 (11.1) years. A total of 47 (72.3%) patients wereAsian.
Efficacy Results:
Objective Response: No patients achieved a complete response (CR). Twenty-seven (41.5%)
patients achieved a partial response (PR). The objective response rate (ORR) (CR+PR) for
the overall population without regard to T790M mutation status was 41.5% (90% confidence
interval [CI]: 31.2%, 52.5%).
Duration of Objective Response (DOR): The median DOR for the overall population was
11.09 (range: 2.70-34.57) months.
Overall Survival (OS): The OS analysis included 9 patients in Japan LIC and Cohort 1 fromPF-06747775 200 mg QD group. The median OS was not estimable since the majority ofpatients were censored. The survival probability at 12 months was 87.5% (90% CI: 50.0%,97.5%).
Progression-Free Survival (PFS): The PFS analysis included 29 patients in PF-06747775
200 mg QD group. Of these, 19 (65.5%) patients had objective progression. The medium
PFS was 8.1 (90% CI: 5.4, 23.3) months. The probability of being event free at 24 months
was 22.8% (90% CI: 9.6%, 39.5%).
Pharmacokinetic Results:
Dose Escalation: The PK of PF-06747775 was observed to be generally proportional to doseover the range of 25 mg to 600 mg following both single and multiple dose administration;
there was no major accumulation or evidence of non-linearity.
Sildenafil Sub-Study: The results demonstrated a minor decrease in area under the plasma
concentration-time profile from time 0 extrapolated to infinite time (AUCinf) and maximum
observed plasma concentration (Cmax) of sildenafil by approximately 34% and 17%,
respectively, when co-administered with PF-06747775, suggesting potential weak inductionof cytochrome P450 (CYP)3A with multiple doses of PF-06747775.
Itraconazole Sub-Study: The results demonstrated a slight increase in dose-normalized area
under the concentration-time profile from time 0 to time tau (AUCtau[dn]) anddose-normalized Cmax (Cmax[dn]) of PF-06747775 by approximately 16% and 22%,
respectively, when co-administered with itraconazole, suggesting CYP3A-based metabolism
is a contributor to the elimination of PF-06747775 following multiple doses. This degree ofincrease in PF-06747775 exposure is not expected to be clinically meaningful.
Esomeprazole Sub-Study: The results demonstrated a slight decrease in PF-06747775 area
under the concentration-time profile from time 0 to time tau (AUCtau) and Cmax by
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Protocol B7971001

CLINICAL STUDY REPORT SYNOPSIS
approximately 17% and 22%, respectively, when co-administered with esomeprazole,suggesting an increase in gut pH may slightly decrease the absorption of PF-06747775
following oral dosing. This degree of decrease in PF-06747775 exposure is not expected tobe clinically meaningful.
PF-06747775 in Combination With Palbociclib: There was no evidence of changes in the PKof PF-06747775 when administered in combination with palbociclib 100 mg QD comparedto administration alone. Due to the very limited palbociclib concentration data in few
patients, no further interpretation is made at this time regarding palbociclib PK behavior
when given under this dose regimen in combination with PF-06747775.
PF-06747775 in Japanese-Only Patients: The PK of PF-06747775 in Japanese patients was
similar between the 2 cohorts (Japan RP2D and Japan PK) following single and multiple
dose administration.
Safety Results:
Dose Limiting Toxicity (DLTs): No DLTs were observed in the dose escalation cohorts andthe Japan LIC. Two patients in Cohort 2A had DLTs.
Adverse Events (AEs): All 65 treated patients had at least 1 all-causality treatment-emergent
adverse event (TEAE) and 61 of them had at least 1 treatment-related TEAE. In the overall
population, the most frequently reported all-causality AEs were diarrhea and paronychia.
Both diarrhea and paronychia were experienced by 45 (69.2%) patients each and all of these
events were considered as treatment-related AEs. Other frequent AEs included
rash (39 [60.0%] patients), stomatitis (30 [46.2%] patients), dermatitis acneiform(28 [43.1%] patients) and dry skin (27 [41.5%] patients). Grade 5 AEs were reported for3 patients, none of which were related to study treatment. The frequency of treatment-related
serious adverse events (SAEs) reported for this study was low (6 [9.2%] patients).
Other safety evaluations: The most frequent shifts from Grade ≤2 at baseline to Grade 3 or 4
post-baseline for hematology laboratory results were lymphopenia (8 [12.3%] patients) andanemia (5 [7.7%] patients). The most frequent shift from Grade ≤2 at baseline to Grade 3 or
4 post-baseline for chemistry results was hyponatremia (8 [12.3%] patients). No patientswere observed with a post-dose corrected QT for heart rate using Fridericia’s formula (QTcF)≥500 msec or a maximum increase from baseline of QTcF ≥60 msec.
Conclusions:•No DLTs were observed in dose escalation cohorts and Japan LIC. Two patients inCohort 2A had DLTs. The maximum tolerated dose (MTD) was not determined.

•PF-06747775 had a safety profile that was generally tolerable and manageable by dosinginterruption, dose reduction, and/or standard medical therapy in patients with advanced

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Protocol B7971001

CLINICAL STUDY REPORT SYNOPSIS
EGFRm NSCLC. No notable findings in laboratory parameters and electrocardiogram(ECG) data were reported.
•

PF-06747775 provided clinically benefit for the total population as evidenced by
Investigator-assessed ORR of 41.5% (90% CI: 31.2%, 52.5%) and median DOR of
11.09 (range: 2.70-34.57) months.

•Following single and multiple-dose administration, plasma PF-06747775 exposures
based on geometric mean AUCtau(dn) and Cmax(dn) were generally proportional to doseover the range of 25 to 600 mg QD.

•In the Japan LIC following repeat oral administration for 11 days (Japan RP2D cohort)and 15 days (Japan PK cohort) in Cycle 1, plasma PF-06747775 exposures (based onAUCtau[dn] and Cmax[dn]) were similar between the 2 cohorts.

•Co-administration of multiple doses of PF-06747775 QD with a proton pump inhibitor(PPI) (esomeprazole), a strong CYP3A inhibitor (itraconazole), or a sensitive CYP3A
substrate (sildenafil), were not associated with clinically meaningful DDIs.

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