Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

Sponsor: Pfizer, Inc.
Investigational Product: Sunitinib malate (SU011248, SUTENT)Clinical Study Report Synopsis: Protocol A6181202
Protocol Title: A single-arm open-label international multi-center study of the efficacy andsafety of sunitinib malate (SU011248, SUTENT) in patients with progressive advanced
metastatic well-differentiated unresectable pancreatic neuroendocrine tumors
Investigators:(* did not randomize patients)
Study Centers: Australia (2 sites), Belgium (1 site), China (9 sites), Czech Republic(2 sites), Estonia (1 site), France (3 sites), Hungary (1 site), India (1 site), Italy (2 sites),
Japan (2 sites), Norway (1 site), Netherland (1 site), Poland (2 sites), Portugal (1 site),
Romania (2 sites), Slovakia (1 site), South Africa (1 site), Spain (2 sites), United States(4 sites)
Publications Based on the Study: None
Study Initiation and Completion Dates: First Patient First Visit: 06 June 2012 to ongoingat data cutoff 19 March 2016
Report Date: 11 November 2016
Previous Report Dates: 07 October 2016
Phase of Development: Phase 4
Study Objectives:
Primary Objective
To confirm sunitinib treatment effect on progression-free survival (PFS) per investigatorassessment in patients with advanced/metastatic, well-differentiated, unresectable pancreatic
neuroendocrine tumors (pNETs) per Response Evaluation Criteria in Solid Tumors(RECIST 1.0).

PFIZER CONFIDENTIAL
Page 1

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

Secondary Objectives•

To assess PFS per independent radiological review;•

To assess time to tumor progression (TTP);•

To assess overall survival (OS);•To assess objective response rate (ORR);•

To assess duration of response (DoR);•To assess time to tumor response (TTR);•

To evaluate the use of Choi criteria;•

To evaluate Chromogranin A (CgA) response;•

To assess the safety and tolerability of sunitinib;•

To assess patient-reported outcomes (PROs);•

To explore the potential relationship between plasma soluble kinase insert domain fortyrosine (sKIT) levels and measures of efficacy including PFS;•

To assess sunitinib and SU12662 (active metabolite of sunitinib) plasma troughconcentrations (Ctrough) and to potentially explore the relationship between Ctrough andsafety, biomarker, and efficacy.

METHODS
Study Design: This study was a multinational, multi-center, open-label, Phase 4 clinical trial
evaluating the efficacy and safety of sunitinib in patients with progressive,advanced/metastatic well-differentiated, unresectable pNETs.
A minimum target enrollment of approximately 80 men and women 18 years of age or older
with progressive advanced/metastatic well-differentiated unresectable pNETs wasestablished for this study population. Of these 80 patients, approximately 40 patients were
not to have received any previous systemic therapies (ie, first-line systemic treatment-naïve
cohort), including chemotherapy, immunotherapy, intravenous peptide receptor radiotherapy,
or investigational anticancer agent other than somatostatin analogs. The remaining
approximately 40 patients were to have experienced progressive disease on or after priorsystemic therapy (ie, later-line/previously treated).
Patients had to have experienced documented disease progression within a year prior to thestart of study enrollment. Eligible patients were enrolled to receive sunitinib orally at
PFIZER CONFIDENTIAL
Page 2

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

37.5 mg once a day on a continuous daily dosing (CDD) schedule. After discontinuation oftreatment and mandated 28-day follow-up, patients were followed to collect information on
further antineoplastic therapy and survival.
Diagnosis and Main Criteria for Inclusion: Patients were to be 18 years of age or older;
have proven diagnosis of well-differentiated pNET with available Ki-67 index, andunresectable or metastatic disease documented on a scan and disease progression within
12 months prior to study enrollment. Presence of at least one measurable target lesion
according to RECIST 1.0; adequate organ function; and Eastern Cooperative Oncology
Group (ECOG) performance status of 0 or 1.
Study Treatment:
Eligible subjects were enrolled to receive sunitinib orally at 37.5 mg once a day on a CDD
regimen. Study medication, sunitinib, was supplied as hard gelatin oral capsules containing
12.5 mg and 25 mg equivalents of sunitinib free base. Cycles were defined as a 28-day
period.
Efficacy Evaluations:Primary Efficacy Endpoint:
PFS per investigator assessment according to RECIST 1.0: time from date of enrollment tofirst progression of disease or death for any reason in the absence of documented progressive
disease (PD), whichever occurred first. If tumor progression data included more than 1 date,
the first date was used. PFS (in months) was calculated as (first event date − enrollment date+1)/30.4.
Secondary Efficacy Endpoints:
PFS per independent radiological review according to RECIST 1.0: time from enrollment tofirst documentation of objective tumor progression or to death due to any cause, whicheveroccurred first.
TTP: time from enrollment to first documentation of objective tumor progression. If tumor
progression data included more than 1 date, the first date was used. TTP (in months) was
calculated as (first event date − enrollment date +1)/30.4.
TTR: time from date of enrollment to first documentation of objective tumor response thatwas subsequently confirmed. For patients proceeding from partial response (PR) to complete
response (CR), the onset of PR was taken as the onset of response. If lesion assessment data
included more than 1 date, the first date was used. TTR (in months) was calculated as (first
response date – enrollment date + 1)/30.4. TTR was only calculated for the subgroup ofpatients with an objective tumor response.

PFIZER CONFIDENTIAL
Page 3

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

OS: time from date of enrollment to date of death due to any cause. OS (in months) was
calculated as (date of death − enrollment date +1)/30.4. For patients still alive at the time of
the analysis or without confirmation of death, the OS time was censored on the last date they
were known to be alive. Patients lacking data beyond enrollment had their OS times
censored at enrollment with a duration of 1 day.
DoR: time from the first documentation of objective tumor response (CR or PR) that was
subsequently confirmed to the first documentation of objective tumor progression or to death
due to any cause, whichever occurred first. If tumor progression data included more than 1
date, the first date was used. DoR was calculated as (the end date for DoR − first CR or PR
that was subsequently confirmed +1)/30.4. DoR (in months) was only calculated for the
subgroup of patients with a confirmed objective tumor response. For patients proceedingfrom PR to CR, the onset of PR was taken as the onset of response.
ORR: percent of patients with confirmed CR or confirmed PR according to the RECIST 1.0,
relative to all enrolled patients. Confirmed responses were those that persisted on repeat
imaging study at least 4 weeks after initial documentation of response. Designation of best
response of stable disease (SD) required the criteria to be met at least 6 weeks after
enrollment. Patients who did not have on-study radiographic tumor re-evaluation, whoreceived antitumor treatment other than the study medication prior to reaching a CR or PR, or
who died, progressed, or dropped out for any reason prior to reaching a CR or PR werecounted as non-responders in the assessment of ORR.
CgA response rate: percent of patients with a confirmed CgA CR or confirmed CgA PR,
relative to the population with an elevated baseline CgA value. CR was defined as adecrease from a high baseline value to one that fell within the normal range, and a PR was
defined as a decrease from a high baseline value to one that was at least 50% lower, but
remained greater than the ULN range for CgA. PD was defined as at least a 50% increase in
CgA level. Confirmed responses were those that persisted at least 4 weeks after initial
documentation of response. Designation of best response of SD required the documentationof SD (<50% increase and <50% decrease from baseline) for at least 6 weeks.
Pharmacokinetic, Pharmacodynamic, and/or Other Evaluations:Plasma samples for determination of sKIT concentrations were obtained pre-dose on Days 1
and 15 of Cycle 1, Cycle 2 Day 1, Cycle 3 Day 1, and then every 2 cycles thereafter (Cycles
5, 7, 9, etc), and at the End of Treatment or time of investigator-assessed disease progression
whenever possible.
Analysis of plasma samples was conducted at Intertek Pharmaceutical Services (Alta
Bioscience Ltd). The sKIT was analyzed using an Enzyme-Linked Immunosorbent Assay(ELISA) kit.
In cases where readings were below the level of quantification (BLQ) for the assay, suchreadings have been excluded from the analyses.
PFIZER CONFIDENTIAL
Page 4

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

Ki-67 tumor index was collected at Screening as part of medical history. Ki-67 assessments
based on previous tumor biopsy results or previous surgical resections had to be provided.
Plasma samples for determination of the trough concentrations (pre-dose) levels of sunitinib
and SU012662 were obtained pre-dose at Day 15 of Cycle 1 and Day 1 of Cycles 2, 3, and 5.
For each PK sample, actual time and date of sample collection in addition to the actual timeand date of the last dose before sample collection were appropriately recorded on the casereport form. Samples were analyzed using validated analytical methods in compliance with
Pfizer standard operating procedures.
A 4 mL blood sample Prep D1 (dipotassium ethylenediamine tetraacetic acid whole bloodcollection optimized for deoxyribonucleic acid analysis) was collected at the baseline visit
and retained for potential pharmacogenomic analyses related to drug response. For example,
putative safety biomarkers, drug metabolizing enzyme genes, drug transport protein genes, orgenes thought to be related to the mechanism of drug action may be examined.
The retained pharmacogenomic samples were collected from all patients unless prohibited by
local regulations.
Patient-reported outcomes (PROs) defined as health-related quality of life (QoL) using theself-administered European Organization for Research and Treatment of Cancer Quality ofLife Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC QLQ Gastrointestinal (GI)NET-21 (EORTC QLQ-G.I.NET21). The questionnaire was to be self-administered by thepatient in the clinic. The questionnaire was to be completed before any interventions (eg,laboratory assessments or study drug administration) at baseline, every cycle post-baseline
assessment including at the End of Treatment or withdrawal, and the visit 28 days
post-treatment. In the event the patient was unable to visit the clinic for the 28 days
post-treatment visit, assessments were not applicable.
Safety Evaluations: Safety evaluations included clinical monitoring, vital signs (heart rate,
blood pressure, temperature, weight), 12-lead electrocardiograms (ECGs), adverse events(AEs), safety laboratory tests, ECOG performance status, physical examination.
Statistical Methods: Detailed methodology for summarization and statistical analyses of thedata collected in this trial was documented in a Statistical Analysis Plan (SAP).
RESULTS
Patient Disposition and Demography: A total of 123 patients were screened for thisstudy (A6181202), of whom 106 received sunitinib treatment (61 patients in thetreatment-naïve cohort and 45 patients in the later-line cohort). Sixty-eight (68) patientswere still ongoing (either on treatment or in long-term survival follow-up) at the time of data
cutoff (Table S1).

PFIZER CONFIDENTIAL
Page 5

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

Table S1. Patient Disposition
Screened = 123
Assigned to Study
TreatedDiscontinued from Study
Patient Died
Relation to Study Drug not Defined
Lost to Follow-up
Other
Patient Refused Further Follow-up
Ongoing at Date of Cutoff

Treatment-Naïve
CohortN(%)
61
61(100.0)16(26.2)
10(16.4)
6
(9.8)
4
(6.6)
0
2
(3.3)
45
(73.8)

Later-Line
CohortN(%)
45
45(100.0)

N
106
106

22
19
3
1
2
0
23

38
29
9
5
2
2
68

(48.9)(42.2)
(6.7)
(2.2)
(4.4)
(51.1)

Total(%)(100.0)(35.8)(27.4)
(8.5)
(4.7)
(1.9)
(1.9)
(64.2)

Discontinuations from Treatment
43(70.5)
39(86.7)
82(77.4)
Patient Died
1
(1.6)
1
(2.2)
2
(1.9)
Relation to Study Drug not Defined36(59.0)
30(66.7)
66(62.3)
Global Deterioration of Health Status
2
(3.3)
2
(4.4)
4
(3.8)
Objective Progression or Relapse
26(42.6)
23(51.1)
49(46.2)
Other
4
(6.6)
4
(8.9)
8
(7.5)
Patient Refused Continued Treatment
4
(6.6)
1
(2.2)
5
(4.7)
for Reason Other Than Adverse Event
Related to Study Drug
4
(6.6)
5
(11.1)
9(8.5)
Adverse Event
4
(6.6)
5
(11.1)
9(8.5)
Not Related to Study Drug
2
(3.3)
3
(6.7)
5
(4.7)
Adverse Event
2
(3.3)
3
(6.7)
5
(4.7)
Full Analysis Set = all patients who were enrolled into the study regardless of whether patients received
study drug or not.
Safety Analysis Set = all patients who received at least 1 dose of study medication.
Note: Percentage is based on the enrolled number of patients in each cohort.

All 106 patients enrolled into the study comprised the full analysis set (FAS) and wereanalyzed for efficacy, 61 patients in the treatment-naïve cohort and 45 patients in thelater-line cohort. All patients in the FAS received at least a dose of sunitinib and were also
included in the safety analysis set.
Data from the 61 treatment-naïve patients in the FAS were combined with the data from thetreatment-naïve patients in the intention-to-treat population in A6181111 for the primary PFS
analysis and pre-defined secondary efficacy analyses (ORR and OS). There were76 first-line patients (41 treated with sunitinib and 35 treated with placebo) in
Study A6181111. Thus, in the combined data there were 102 treatment-naïve patients thatreceived sunitinib and 35 patients that received placebo.
The overall FAS population of this study was comprised of 63 (59.4%) male and 43 (40.6%)
female patients. The mean age, mean weight, and mean height of the FAS were 54.6 years,
70.3 kg, and 169.1 cm, respectively. The majority of the demographic and baseline
PFIZER CONFIDENTIAL
Page 6

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

characteristics were similar between the 2 cohorts; however, the proportion of female andAsian patients was smaller in the later-line cohort.
All patients had an ECOG PS of 0 (64.2%) or 1 (35.8%) at baseline without notabledifferences between the 2 cohorts.
All patients had measurable disease at baseline and adequate baseline assessment. Overall,
the majority of patients had lesions in the liver (98 [92.5%] patients) and pancreas(47 [44.3%] patients). Patients most commonly had 1, 2 or 3 involved disease sites. The
treatment-naïve cohort had a larger proportion of patients with 1 involved disease site,
compared to the later-line cohort (39.3% and 20.0%, respectively). A smaller proportion ofpatients in the treatment-naïve cohort had lesions in the pancreas (36.1%) than in thelater-line cohort (55.6%).
Prior somatostatin analog therapy (SSA) was reported for 51 (48.1%) patients with24 (39.3%) patients in the treatment-naïve cohort and 27 (60.0%) patients in the later line
cohort. Patients with regimens that consisted only of SSAs were considered naïve.
In regards to loco regional treatment at screening, the most common were trans arterial
chemoembolization (treatment-naïve cohort: 23.0%; later line cohort: 13.3%) followed byradiofrequency ablation (treatment-naïve cohort: 1.6%); later-line cohort: 6.7%). Patients
who received previous chemoembolization without exposure to prior systemic chemotherapy
were considered treatment-naïve.
In general, the demographic characteristics from Study A6181111 were comparable to thetreatment-naïve cohort in this study (A6181202).
Efficacy Results:
Study A6181202 Alone
The primary analysis showed that the median PFS as assessed by investigator was
13.2 months (95% CI: 10.9, 16.7). The median PFS as assessed by investigator was
13.2 months (95% CI: 7.4, 16.8) and 13.0 months (95% CI: 9.2, 20.4) in the treatment-naïve
cohort and the later-line cohort, respectively (Table S2). A median PFS of 11.1 months (95%
CI: 7.4, 16.6) was observed in the FAS based on the independent third-party radiology
assessment according to RECIST 1.0 with a median PFS of 11.1 months (95% CI: 5.5, 16.7)
in the treatment-naïve cohort and 9.5 months (95% CI: 7.4, 18.4) in the later-line cohort. The
third-party assessments supported the primary investigator-assessed PFS analysis.

PFIZER CONFIDENTIAL
Page 7

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

Table S2

Progression-Free Survival (Based on the Investigator Assessment
According to RECIST) Treatment-Naive Cohort vs. Later-Line Cohort Full Analysis Set
Treatment-Naive
Cohort(N=61)
37 (60.7)

Later-Line
Cohort(N=45)
28 (62.2)

65 (61.3)

35 (57.4)
2 (3.3)26 (57.8)
2 (4.4)61 (57.5)
4 (3.8)

Number censoredReason for censorship
No adequate baseline assessments
No on-study disease assessments
Given new anti-cancer treatment prior totumor progression
Unacceptable gap of >16 weeks between PD
or Death to the most recent prior adequate
assessment
In follow-up for progression
Removed from Study prior Documentationof PD or Death

24 (39.3)

17 (37.8)

41 (38.7)

00
2 (3.3)00
6 (13.3)

00
8 (7.5)0

3 (6.7)3 (2.8)18 (29.5)
4 (6.6)6 (13.3)
2 (4.4)24 (22.6)6 (5.7)

Probability of being event free at Month 6a(95% CIb)

66.7 [52.9, 77.4]

75.9 [58.7, 86.7]

70.5[60.2, 78.7]

Number with event
Type of event
Progression of disease (PD)Death without progression of disease

Total(N=106)

Kaplan-Meier estimates of Progression Free
Survival (Month) Quartiles (95% CI)c25%
5.0 [2.7, 7.4]
7.4 [3.7, 10.2]
5.6 [3.7, 7.5]
50%
13.2 [7.4, 16.8]
13.0 [9.2, 20.4]
13.2 [10.9, 16.7]
75%
20.2 [16.7, 26.2]
22.9 [14.7, 37.9]
22.9 [16.8, 33.2]
Abbreviations: CI = Confidence Interval; PD = Progression of Disease; PFS = Progression-Free Survival;
RECIST= Response Evaluation Criteria In Solid TumorsaEstimated from the Kaplan-Meier curve.
bCalculated from the product-limit method.
cCalculated from Brookmeyer and Crowley Method.
PFS is defined as the time from date of enrollment to first progression of disease (PD) or death for any
reason in the absence of documented PD, whichever occurs first.

Comparisons were made regarding the independent third-party radiology assessment
according to Choi criteria in addition to RECIST; the evaluation of tumor response according
to Choi criteria has been considered particularly useful in patients with GIST to also capturechanges in tumor density after treatment. A longer median PFS was observed in both cohortscompared to RECIST, with a median PFS of 18.7 months (95% CI: 5.6, not estimable) in thetreatment-naïve cohort, and a median PFS of 16.5 months (95% CI: 7.4, 22.9) in the later-line
cohort.

PFIZER CONFIDENTIAL
Page 8

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

Analyses of secondary efficacy endpoints supported the primary PFS analysis. The median
TTP based on investigator assessment was 14.5 months (95% CI: 11.0, 16.7) in the FAS,
with a median TTP of 14.8 months (95% CI: 7.5, 16.8) and 14.5 months (95% CI: 9.2, 20.4)
for the treatment-naïve cohort and later line cohort, respectively. RECIST 1.0 confirmed
ORR in the FAS based on investigator assessment was 24.5% (95% exact CI: 16.7, 33.8)
with a CR rate of 2.8% and a PR rate of 21.7%. The ORR was 21.3% (95% exact CI: 11.9,
33.7) in the treatment-naïve cohort and 28.9% (95% exact CI: 16.4, 44.3) in the later line
cohort. Responses were rapid, with a median TTR based on investigator assessment was 3.8
months (range: 1.0-11.1 months); there was no difference in median TTR between thetreatment-naïve cohort and the later line cohort (both medians 3.8 months). Responses werealso durable, with a median DoR based on investigator assessment of 14.7 months (95% CI:
10.1, 21.9); the median DoR in the treatment-naïve cohort was longer (19.1 months [95% CI:
10.1, not estimable]) than the median DoR in the later-line cohort (14.7 months [95% CI: 5.5,
21.9]).
In addition to PFS analysis according to Choi criteria, TTP was also analysed according toChoi and the median was 18.7 months (95% CI: 5.6, not estimable) for the treatment-naïve
cohort and 16.7 months (95% CI: 7.4, 30.9) for the later-line cohort; which was greater than
the investigator-assessed TTP by RECIST 1.0.. Furthermore, the ORR based on the
independent third-party radiology assessment according to Choi criteria was higher than the
ORR assessments according to RECIST 1.0: 52.5% (95% exact CI: 39.3, 65.4) and 55.6%(95% exact CI: 40.0, 70.4) in the treatment-naïve and later-line cohort, respectively.
Although there was a trend in evaluating higher treatment response when Choi criteria werecompared to RECIST criteria; however, further analysis is warranted to determine the role
Choi criteria may play in assessing response in patients with pNET.
As the majority of patients were in follow-up at the time of data cutoff, the OS data were notmature as of the data cutoff date. An updated analysis of OS will be performed when the
median OS can be accurately calculated and presented in a supplemental CSR.
In patients with confirmed CgA response, a greater proportion of patients in thetreatment-naïve cohort had a confirmed objective CR or PR (16.4% [95% exact CI: 9.6,
32.5]) compared to the later line cohort (11.1% [95% exact CI: 4.0, 25.6]). However, adefinitive conclusion on CgA response could not be made, as the sample size was small.
Combined Studies A6181202 and A6181111 Data
To strengthen the confirmed sunitinib treatment effect on PFS demonstrated in Study
A6181202, PFS data from treatment-naïve patients in this study and Study A6181111 werecombined and compared to PFS data from the placebo control arm of Study A6181111. A
statistically significant and clinically meaningful improvement in investigator-assessed PFS
was observed in favor of patients receiving sunitinib (ie, sunitinib arm treatment-naïve
cohort) compared to patients receiving placebo (ie, placebo arm treatment-naïve cohort). A
median PFS of 12.9 months (95% CI: 7.4, 16.7) was observed in the sunitinib arm
treatment-naïve cohort, and a median PFS of 5.7 months (95% CI: 3.6, 7.9) was observed in
PFIZER CONFIDENTIAL
Page 9

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

the placebo arm treatment-naïve cohort, with an HR of 0.429 (95% CI: 0.245, 0.752) and a
1-sided p-value of 0.001 based on 50 events in the sunitinib arm treatment-naïve cohort and19 events in the placebo arm treatment-naïve cohort. In order to ensure that the PFS
endpoint was robust, an independent third-party radiology assessment according to RECIST
1.0 was conducted. A median PFS of 12.6 months (95% CI: 7.7, 16.6) was observed for thesunitinib arm treatment-naïve cohort and a median of 6.2 months (95% CI: 3.6, 8.1) for theplacebo arm treatment-naïve cohort, with an HR of 0.552 (95% CI: 0.292, 1.042) and a
1-sided p-value of 0.031 based on 55 events (sunitinib arm treatment-naïve cohort: 41[40.2%], placebo arm treatment-naïve cohort: 14 [40.0%]), which supported the robustnessof the results of the primary investigator-assessed PFS analysis.
Controlling for baseline characteristics (age, ethnic origin, and performance status of PFS as
assessed by Investigator) had no effect on the PFS HR as assessed by investigator (HR=0.424[95% CI: 0.217, 0.827]) with a 1-sided p value of 0.005. The results of the sensitivity
analysis supported the robustness of the primary analysis.
Patient-Reported Outcomes
The naïve cohort showed some declines in health-related QoL compared to the later-line
cohort; however these changes manifest in later cycles. Conversely, the later-line cohort
does not show notable declines in scales. In addition, both cohorts showed progressive
decline in social functioning over time.
The combined cohort was not meaningful due to the scarcity of data from latter cycles from
Study A6181111.
Pharmacokinetic and Pharmacodynamic Results:
Biomarkers
SKIT concentration was pharmacodynamically modulated upon sunitinib treatment. Thisobservation is consistent with previous reports in patients with metastatic breast cancer and
GIST. No statistically significant differences were seen when PFS curves were comparedafter stratification by median baseline sKIT concentration in the treatment-naïve and in thelater-line cohorts. In the OS analysis in the treatment-naïve cohort, while OS data are still
immature, the Kaplan-Meier estimate showed a potential trend in favor of patients withbaseline sKIT ≥ median. However, this observation was not replicated in the later-line
cohort but held in the combined cohorts.
No statistically significant differences were seen when PFS curves were compared after
stratification by median baseline tumor Ki-67 index in the treatment-naïve and in thelater-line cohorts. When OS curves were compared after stratification by median baseline
tumor Ki-67 index in the treatment-naïve cohort, and while OS data are still immature, theKaplan Meier estimation showed a trend in favor of the group with baseline tumor Ki-67
index ≥ median. However, this trend was not observed in the later-line cohort or in the
PFIZER CONFIDENTIAL
Page 10

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

combined cohorts. This observation is consistent with previous reports which showedsunitinib and/or everolimus may induce durable disease control in patients withwell-differentiated pNET with a Ki-67 index above 15% and positive lesions on functional
imaging with gallium68 dotatoc and/or Octreoscan.
In summary, there were no clear predictive and/or prognostic biomarkers identified in thisstudy for patients with advanced/metastatic, well-differentiated, unresectable pNETs withregard to PFS. With regard to OS, potential associations were observed in relation tobaseline sKIT and Ki-67 index in the treatment-naïve cohort; however, the OS results are still
immature and based on only few events. In addition, in the later-line cohort, the OS
appeared to be similar between the sKIT or Ki-67 subgroups.
Pharmacokinetics and Pharmacokinetics-Pharmacodynamics
Another secondary objective of this study was to determine the Ctrough values for sunitinib
and its active metabolite SU012662 in pNET patients and to potentially explore therelationship between Ctrough values and safety, efficacy, and biomarkers. Both sunitinib andits active metabolite appeared to reach steady state concentrations by Day 15 of Cycle 1.
There appeared to be no additional accumulation of sunitinib and its active metabolite acrosssubsequent cycles. Based on the results of the analyses exploring potential relationships
between safety, efficacy, and biomarker parameters with Total Drug Ctrough values on Day 15of Cycle 1 and Day 1 of Cycles 2 and 3, there appeared to be weak correlations (ie, r < 0.50)
between safety (ie, percent change from baseline in absolute neutrophil count, thrombocyte
count, lymphocyte count, hemoglobin, and systolic blood pressure count) and biomarker (ie,fold change from baseline in sKIT) parameters with Ctrough values. In addition, the incidenceof any-grade palmar-plantar erythrodysesthesia syndrome, thrombocytopenia, hypertension,and anaemia appeared to be greater in patients with higher Total Drug Ctrough values (ie, ≥median Ctrough) as compared to those with lower Total Drug Ctrough values (ie, < medianCtrough). Furthermore, the ORR (based on RECIST or CgA criteria) and median PFS
appeared to be greater in patients with higher Total Drug Ctrough values as compared to thosewith lower Total Drug Ctrough values. There were no consistent trends with respect to median
OS in patients with higher Ctrough values as compared to those with lower Ctrough values.
Further analyses showed no correlations (ie, -0.3<r<0.3) between PFS or OS with Ctroughvalues on Day 15 of Cycle 1 and Day 1 of Cycles 2 and 3.
Safety Results:
One hundred four (104) patients (98.1%) experienced at least 1 AE on sunitinib treatment,
and 69 patients (65.1%) experienced Grade 3 or 4 AEs, which were generally manageable bydosing interruption (63.2%), dose reduction (18.9%), and/or supportive care. Neutropenia,
diarrhoea, leukopenia, palmar-plantar erythrodysaesthesia syndrome, fatigue, andthrombocytopenia were the most commonly all-causality reported AEs. The most common
treatment-related AEs in this study were consistent with those that have previously beenreported with sunitinib, such as neutropenia, diarrhoea, leukopenia, thrombocytopenia, andpalmar-plantar erythrodysaesthesia syndrome (Table S3). Twenty-six (26) patients (24.5%)
PFIZER CONFIDENTIAL
Page 11

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

experienced SAEs. Eighteen (18) patients (17%) discontinued treatment due to AEs, 10 of
the 18 patients discontinued due to treatment-related AEs. There were no deaths due totreatment-related toxicity and all deaths were due to disease progression with the exceptionof 1 death in the later-line cohort with reason not clearly ascertainable. The sunitinib AE
profile observed in this study was generally consistent with the known AE profile forsunitinib. There were no new safety findings identified in this study compared to those in
Study A6181111 and previously reported sunitinib studies.
In summary, the sunitinib treatment effect was confirmed in patients withadvanced/metastatic, well-differentiated, unresectable pNETs with an acceptable safety
profile. The benefit/risk profile of sunitinib was confirmed to be favorable for this patient
population.
Table S3. Summary of Key Treatment-Emergent Adverse Events Experienced by≥15% of Patients in Any Cohort by Preferred Term, and Corresponding
CTCAE Grade (Treatment-Related, All Cycles, All Grades and Grade 3/4)
Treatment-Naïve
Cohort(N=61)All
Grade
Grades3/4
36 (59.0) 12 (19.7)
29 (47.5)5 (8.2)25 (41.0)
4 (6.6)Later-Line Cohort(N=45)All
Grade
Grades3/4
21 (46.7) 10 (22.2)
20 (44.4)
1 (2.2)21 (46.7)
3 (6.7)

Total(N=106)

Number (%) of Patients with
All
Grade
Preferred Term Adverse Event
Grades
3/4
Neutropenia
57 (53.8)
22 (20.8)
Diarrhoea
49 (46.2)
6 (5.7)
Leukopenia
46 (43.4)
7 (6.6)
Palmar-plantar erythrodysaesthesia
syndrome
19 (31.1)
5 (8.2)14 (31.1)
2 (4.4)33 (31.1)
7 (6.6)
Thrombocytopenia
18 (29.5)
6 (9.8)14 (31.1)
2 (4.4)32 (30.2)
8 (7.5)
Fatigue18 (29.5)
1 (1.6)
10 (22.2)
0 (0.0)28 (26.4)
1 (0.9)Dysgeusia
13 (21.3)
0 (0.0)11 (24.4)
0 (0.0)24 (22.6)
0 (0.0)
Nausea9 (14.8)
0 (0.0)13 (28.9)
1 (2.2)22 (20.8)
1 (0.9)Hypertension
14 (23.0)
4 (6.6)7 (15.6)
2 (4.4)21 (19.8)
6 (5.7)
Stomatitis
13 (21.3)
2 (3.3)6 (13.3)
1 (2.2)19 (17.9)
3 (2.8)Dyspepsia
5 (8.2)0 (0.0)11 (24.4)
0 (0.0)16 (15.1)
0 (0.0)Abbreviations: AE=Adverse event; CTCAE=Common Terminology Criteria for Adverse Events;
MedDRA=Medical Dictionary for Regulatory Activities, N=Number of patients; PT=Preferred term;
TEAE=Treatment Emergent Adverse Event.
Patients are counted once at the highest CTCAE grade on-study.
CTCAE v3.0 was used.
TEAEs are all AEs (serious and non-serious) occurred, for the first time, on or after the first day of study
treatment. Events that are continuations of baseline abnormalities are considered TEAEs only if there is anincrease in grade over baseline.
Maximum CTCAE Grade is defined as the maximum CTCAE grade value for the specific PT.
MedDRA (v19.0) coding dictionary applied.

PFIZER CONFIDENTIAL
Page 12

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS

Conclusions:•

The sunitinib treatment effect was confirmed in patients with advanced/metastatic,well-differentiated, unresectable pNET, with an investigator-assessed median PFS of
13.2 months (95% CI: 10.9, 16.7). The sunitinib treatment effect in for treatment-naïve
pNET patients was strengthened by the combination of PFS data from the treatmentnaïve cohort of Study A6181202 with PFS data from Study A6181111, where
investigator-assessed median PFS of 12.9 months (95% CI: 7.4, 16.7) was observed forthe sunitinib arm treatment-naïve cohort and 5.7 months (95% CI: 3.6, 7.9) was observed
for the placebo arm treatment-naïve cohort with an HR of 0.429 (95% CI: 0.245, 0.752)
and a p-value of 0.001.

•

The independent third-party radiology assessment according to RECIST 1.0 supported
the primary investigator assessed PFS analysis with a median PFS of 11.1 months(95% CI: 7.4, 16.6).

•

The secondary endpoints (TTP and ORR) assessments according to RECIST supported
the primary PFS endpoint with an investigator-assessed median TTP of 14.5 months(95% CI: 11.0, 16.7) and an investigator-assessed ORR of 24.5% (95% exact CI: 16.7,33.8), with responses that were rapid and durable with an investigator-assessed median
TTR of 3.8 months (range: 1.0-11.1 months) and an investigator-assessed median DoR of
14.7 months (95% CI: 10.1, 21.9).

•

Although there was a trend in evaluating higher treatment response when Choi criteria
were compared to RECIST criteria, further analysis is warranted to determine the role
Choi criteria may play in assessing response in patients with pNET.

•

A definitive conclusion on CgA response could not be made, as the sample size wassmall.

•

Sunitinib was associated with AEs that were consistent with the known safety profile,
generally manageable by dosing interruption, dose reduction, and/or supportive care.

•

In terms of global health-related quality of life and functioning domains (EORTCQLQ-C30 and EORTC QLQ-G.I.NET21), the treatment-naïve cohort showed a decline
earlier than the later-line cohort, however, these changes were seen in later cycles.

•

Global health-related quality of life and functioning domains (EORTC QLQ-C30) weremaintained for patients in the sunitinib arm treatment-naïve cohort with limited adverse
symptomatic effects.

•

sKIT concentrations were pharmacodynamically modulated, decreasing steadily while on
sunitinib treatment until Cycle 7, at which time the concentrations reached a low plateau
and did not change notably until the End of Treatment, at which point the concentrations
still remained below the baseline concentrations but started rising again.
PFIZER CONFIDENTIAL
Page 13

Clinical Study Report
Protocol A6181202

2.

CLINICAL STUDY REPORT SYNOPSIS•

sKIT and Ki-67 were not identified as clear predictive and/or prognostic biomarkers inthis study for patients with advanced/metastatic, well-differentiated, unresectable pNETs.

•

Potential associations were observed in regard to OS in relation to baseline sKIT and
Ki-67 index in treatment-naïve pNET patients; however, the OS results are still immatureand based on only few events. In addition, in the later-line pNET patients, the OS
appeared to be similar between the sKIT or Ki-67 subgroups.

•

The steady state concentrations for sunitinib and its active metabolite were reached by
Day 15 of Cycle 1 and did not show additional accumulation across subsequent cycles.

•

The incidence of all grades AEs of palmar-plantar erythrodysaesthesia syndrome,
thrombocytopenia, hypertension, and anaemia appeared to be greater in patients withhigher Total Drug Ctrough concentrations as compared to those with lower Total Drug
Ctrough.

•

The ORR (based on RECIST or CgA criteria) and median PFS appeared to be greater inpatients with higher Total Drug trough concentrations as compared to those with lower
Total Drug trough concentrations.

PFIZER CONFIDENTIAL
Page 14

Supplemental Clinical Study Report
Protocol A6181202

TITLE PAGE
Study Title:

A Single Arm Open-Label International MultiCenter Study
Of The Efficacy And Safety Of Sunitinib Malate (SU011248,
Sutent®) In Patients With Progressive Advanced Metastatic
WellDifferentiated Unresectable Pancreatic Neuroendocrine
TumorsSupplemental Clinical Study Report

Investigational Product:

Sunitinib malate (SU011248, SUTENT®)

Indication:

Pancreatic neuroendocrine tumors

Sponsor:Pfizer Inc.

Protocol Number:

A6181202Phase of Development:

Phase 4

Study Initiation Date:First Patient First Visit (FPFV): 06 June 2012

Primary Completion Date:

19 March 2016

Study Completion Date:

Last Patient Last Visit (LPLV): 26 July 2018

Sponsor’s Signatories:

Clinical Lead: PPD
Statistical Line Head: PPD

Final Signoff Date:

13 Dec 2018

Investigators:

See below.

PFIZER CONFIDENTIAL
Page 1Page 1MD
PhDSupplemental Clinical Study Report
Protocol A6181202
Country

Center Principal Investigator Country

Center Principal Investigator

Australia

CCI *

PPD

Australia

CCI

PPD

Belgium

CCI

PPD

China

CCI

PPD

China

CCI

PPD

China

CCI

PPD

China

CCI

PPD

China

CCI * PPD

China

CCI

PPD

China

CCI

PPD

China

CCI *

PPD

China

CCI

PPD

Czech
Republic

CCI

PPD

Czech
Republic

CCI

PPD

Estonia

CCI *

PPD

FranceCCI

PPD

FranceCCI *PPDFrance

CCI * PPD

Hungary

CCI

PPD

India

CCI

Italy

CCI

PPD

Italy

CCI * PPD

Japan

CCI

PPD

Japan

CCI

NorwayCCIPPD

Netherland CCI * PPDPolandCCI *PPDPolandCCI * PPD

Portugal

CCI *

PPD

Romania

CCI

PPD

Romania

CCI

PPD

Slovakia

CCI

PPD

PFIZER CONFIDENTIAL
Page 2

Page 2PPD

PPD

Supplemental Clinical Study Report
Protocol A6181202
PPD

South
Africa

CCI

PPD

Spain

CCI

Spain

CCI *

PPD

UnitedStates

CCI * PPD

UnitedStatesCCI *PPD

UnitedStates

CCI

UnitedStates

CCI

PPD

PPD

*Did not enrol patients.
Abbreviation: PI = Principle Investigator.
GOOD CLINICAL PRACTICE STATEMENT
This study was conducted in compliance with Good Clinical Practice (GCP) guidelines and,
where applicable, local country regulations relevant to the use of new therapeutic agents inthe country/countries of conduct, including the archiving of essential documents.

PFIZER CONFIDENTIAL
Page 3

Page 3

Supplemental Clinical Study Report
Protocol A6181202
TABLE OF CONTENTS
TITLE PAGE .............................................................................................................................1
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................7
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................15
ETHICS....................................................................................................................................17
Independent Ethics Committee or Institutional Review Board......................................17
Ethical Conduct of the Study .........................................................................................17
INTRODUCTION ...................................................................................................................17
STUDY OBJECTIVES............................................................................................................19
Primary Objective ..........................................................................................................19
Secondary Objectives .....................................................................................................19
INVESTIGATIONAL PLAN..................................................................................................19
Study Design ..................................................................................................................20
Selection of Study Population ........................................................................................20
Inclusion and Exclusion Criteria ..........................................................................20
Treatments ......................................................................................................................21
Efficacy, Pharmacokinetic, and Safety...........................................................................21
Efficacy Evaluations.............................................................................................21
Safety Evaluations ................................................................................................22
Pharmacokinetic Evaluations................................................................................22
Statistical Methods Planned in the Protocol...................................................................22
Data Sets Analyzed ........................................................................................................22
Changes in the Conduct of the Study .............................................................................23
Protocol Amendment 1, dated 31 July 2012.........................................................23
Protocol Amendment 2, dated 25 January 2013...................................................23
Protocol Amendment 3, dated 05 July 2016.........................................................23
Changes in the Planned Analysis ...................................................................................23
RESULTS ................................................................................................................................24
Patient Disposition .........................................................................................................24
Demography ...................................................................................................................26
Protocol Deviations ........................................................................................................27
PFIZER CONFIDENTIAL
Page 4

Page 4

Supplemental Clinical Study Report
Protocol A6181202
Prior and Concomitant Treatments ................................................................................27
Efficacy Results..............................................................................................................27
Overall Survival: Global Population ....................................................................27
Overall Survival: China Subgroup........................................................................32
Pharmacokinetic, Pharmacodynamic and Other Results................................................34
Safety Results .................................................................................................................34
Extent of Exposure ...............................................................................................34
Adverse Events .....................................................................................................40
Brief Summary of Adverse Events.........................................................40
Incidence of Adverse Events..................................................................42
Listing of Adverse Events by Patient .....................................................56
Deaths, Other Serious Adverse Events, and Other Significant Adverse
Events...............................................................................................................57
Deaths.....................................................................................................57
Other Serious Adverse Events................................................................58
Other Significant Adverse Events ..........................................................59
Narratives of Deaths, Other Serious Adverse Events, and Other Significant
Adverse Events ................................................................................................59
Death Narratives.....................................................................................59
Other Serious Adverse Event Narratives ...............................................59
Other Adverse Events Narratives ...........................................................59
Clinical Laboratory Evaluation.............................................................................59
Vital Signs, Electrocardiogram, and Physical Findings .......................................60
Vital Signs ..............................................................................................60
Electrocardiogram Results .....................................................................60
Physical Findings ...................................................................................60
CONCLUSIONS......................................................................................................................60
Efficacy ..........................................................................................................................60
Safety..............................................................................................................................61
REFERENCES ........................................................................................................................64
LIST OF TABLES
Table 1.

Discontinuations from Study Phase (Full Analysis Set) and Treatment
Phase (Safety Analysis Set): Global Population...................................................25
PFIZER CONFIDENTIAL
Page 5

Page 5

Supplemental Clinical Study Report
Protocol A6181202
Table 2.

Discontinuations from Study Phase (Full Analysis Set) and Treatment
Phase (Safety Analysis Set): China Subgroup......................................................26

Table 3.

Overall Survival – Full Analysis Set; Global Population.....................................28

Table 4.

Overall Survival – Treatment-Naïve Cohort in Study A6181202 +Sunitinib Arm Treatment-Naïve Cohort in Study A6181111 versus Placebo
Arm Treatment-Naïve Cohort in Study A6181111 – Full Analysis Set;
Global Population .................................................................................................31

Table 5.

Overall Survival – Full Analysis Set; China Subgroup ........................................33

Table 6.

Duration of Treatment – Safety Analysis Set; Global Population........................35

Table 7.

Summary of Dose Administration – Safety Analysis Set; Global Population .....36

Table 8.

Overall Cumulative Dose and Relative Dose Intensity – Safety Analysis
Set; Global Population..........................................................................................37

Table 9.

Duration of Treatment – Safety Analysis Set; China Subgroup...........................38

Table 10.

Summary of Dose Administration – Safety Analysis Set; China Subgroup ........39

Table 11.

Overall Cumulative Dose and Relative Dose Intensity – Safety Analysis
Set; China Subgroup .............................................................................................40

Table 12.

All-Causality Treatment-Emergent Adverse Events – Safety Analysis Set;
Global Population .................................................................................................41

Table 13.

All-Causality Treatment-Emergent Adverse Events – Safety Analysis Set;
China Subgroup ....................................................................................................42

Table 14.

All-Causality Treatment-Emergent Adverse Events Experienced by 5% ofPatients in Either Cohort by System Organ Class and Preferred Term (All
Cycles, All Grades) – Safety Analysis Set; Global Population ............................43

Table 15.

All-Causality Treatment-Emergent Adverse Events Experienced by
3 Patients by System Organ Class and Preferred Term (All Cycles, All
Grades) – Safety Analysis Set; China Subgroup ..................................................47

Table 16.

Treatment-Related Treatment-Emergent Adverse Events – Safety Analysis
Set; Global Population..........................................................................................49

Table 17.

Treatment-Related Treatment-Emergent Adverse Events – Safety Analysis
Set; China Subgroup .............................................................................................50

Table 18.

Treatment-Related Treatment-Emergent Adverse Events Experienced by≥5% of Patients in Either Cohort by System Organ Class and Preferred
Term (All Cycles, All Grades) – Safety Analysis Set; Global Population...........51

Table 19.

Treatment-Related Treatment-Emergent Adverse Events Experienced by
3 Patients, by System Organ Class and Preferred Term (All Cycles, All
Grades) – Safety Analysis Set; China Subgroup ..................................................55

Table 20.

Summary of Deaths – Safety Analysis Set; Global Population............................57

Table 21.

Summary of Deaths – Safety Analysis Set; China Subgroup...............................58
PFIZER CONFIDENTIAL
Page 6

Page 6

Supplemental Clinical Study Report
Protocol A6181202
LIST OF FIGURES
Figure 1.

Overall Survival – Treatment-Naïve Cohort and Later-Line Cohort - Full
Analysis Set; Global Population...........................................................................29

Figure 2.

Overall Survival – Treatment-Naïve Cohort in Study A6181202 +Sunitinib Arm Treatment-Naïve Cohort in Study A6181111 versus Placebo
Arm Treatment-Naïve Cohort in Study A6181111 - Full Analysis Set ...............32

Figure 3.

Overall Survival – Treatment-Naïve Cohort versus Later-Line Cohort –Full Analysis Set; China Subgroup.......................................................................34

PFIZER CONFIDENTIAL
Page 7

Page 7

Supplemental Clinical Study Report
Protocol A6181202
14. TABLES AND FIGURES REFERRED TO BUT NOT INCLUDED IN THE
TEXT .................................................................................................................................65
NOTE: Since this is a synopsis study report, not all of the tables applicable to a full study
report are necessarily included. Therefore, there may be gaps in the sequences of table
numbers. The report has been carefully reviewed to ensure that all relevant tables arepresent.
14.1 Demographic Data
Table 14.1.1.3

Discontinuations from Study Phase - Full Analysis Set ........... 66

Table 14.1.1.3.1

Discontinuations from Study Phase - Full Analysis Set Chinese Subgroup Analysis ...................................................... 67

Table 14.1.1.4

Discontinuations from Treatment Phase – Safety Analysis
Set ............................................................................................. 68

Table 14.1.1.4.1

Discontinuations from Treatment Phase - Safety Analysis Set- Chinese Subgroup Analysis ................................................... 69

14.2 Efficacy Data Summary
Table 14.2.3.1.1

Overall Survival - Full Analysis Set - Chinese Subgroup
Analysis .................................................................................... 70

Table 14.2.6.1

Overall Survival (Naive Cohort + Sunitinib arm Naïve
Cohort in Study A6181111 vs. Placebo arm Naïve Cohort inStudy A6181111) - Full Analysis Set ....................................... 71

Table 14.2.6.2

Overall Survival (Naïve Cohort vs. Later-Line Cohort) - Full
Analysis Set .............................................................................. 72

Table 14.2.6.3

Overall Survival - Full Analysis Set ......................................... 73

Figure 14.2.2.1.1

Overall Survival - Full Analysis Set - Chinese Subgroup
Analysis .................................................................................... 74

Figure 14.2.5.1

Overall Survival (Naive Cohort + Sunitinib arm Naive
Cohort in Study A6181111 vs. Placebo arm Naive Cohort inStudy A6181111) - Full Analysis Set ....................................... 75

Figure 14.2.5.2

Overall Survival (Naive Cohort vs. Later-Line Cohort) - Full
Analysis Set .............................................................................. 76

PFIZER CONFIDENTIAL
Page 8Page 8

Supplemental Clinical Study Report
Protocol A6181202
14.3 Safety Data Summary
14.3.1 Adverse Events
Table 14.3.1.2.1

Treatment-Emergent Adverse Events (All Causalities) Safety Analysis Set ................................................................... 77

Table 14.3.1.2.1.1

Treatment-Emergent Adverse Events (All Causalities) Safety Analysis Set - Chinese Subgroup Analysis ................... 79

Table 14.3.1.2.9.1

Summary of Treatment-Emergent Adverse Events by
MedDRA System Organ Class, Preferred Term, andMaximum CTCAE Grade (All Causalities, All Cycles) Safety Analysis Set ................................................................... 81

Table 14.3.1.2.9.1.1

Summary of Treatment-Emergent Adverse Events by
MedDRA System Organ Class, Preferred Term, andMaximum CTCAE Grade (All Causalities, All Cycles) Safety Analysis Set - Chinese Subgroup Analysis ................... 115

Table 14.3.1.2.9.5

Summary of Treatment-Emergent Adverse Event: Thyroid
Dysfunction by Maximum CTCAE Grade (All Causalities,
All Cycles) - Safety Analysis Set ............................................. 133

Table 14.3.1.2.9.5.1

Summary of Treatment-Emergent Adverse Event: Thyroid
Dysfunction by Maximum CTCAE Grade (All Causalities,
All Cycles) - Safety Analysis Set - Chinese Subgroup
Analysis .................................................................................... 136

Table 14.3.1.2.9.6

Summary of Treatment-Emergent Adverse Event: Result of
TSH by Maximum CTCAE AE Grade (All Causalities, All
Cycles) - Safety Analysis Set ................................................... 139

Table 14.3.1.2.9.6.1

Summary of Treatment-Emergent Adverse Event: Result of
TSH by Maximum CTCAE AE Grade (All Causalities, All
Cycles) - Safety Analysis Set - Chinese Subgroup Analysis.... 142

Table 14.3.1.2.9.7

Summary of Treatment-Emergent Adverse Event:Proteinuria by Maximum CTCAE AE Grade (All Causalities,
All Cycles) - Safety Analysis Set ............................................. 144

Table 14.3.1.2.9.7.1

Summary of Treatment-Emergent Adverse Event:Proteinuria by Maximum CTCAE AE Grade (All Causalities,
All Cycles) - Safety Analysis Set - Chinese Subgroup
147
Analysis ....................................................................................

PFIZER CONFIDENTIAL
Page 9Page 9

Supplemental Clinical Study Report
Protocol A6181202
Table 14.3.1.3.1

Treatment-Emergent Adverse Events (Treatment Related) Safety Analysis Set ................................................................... 150

Table 14.3.1.3.1.1

Treatment-Emergent Adverse Events (Treatment Related) Safety Analysis Set - Chinese Subgroup Analysis ................... 152

Table 14.3.1.3.9.1

Summary of Treatment-Emergent Adverse Events by
MedDRA System Organ Class, Preferred Term, andMaximum CTCAE Grade (Treatment Related, All Cycles) Safety Analysis Set ................................................................... 154

Table 14.3.1.3.9.1.1

Summary of Treatment-Emergent Adverse Events by
MedDRA System Organ Class, Preferred Term, andMaximum CTCAE Grade (Treatment Related, All Cycles) Safety Analysis Set - Chinese Subgroup Analysis ................... 181

14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events
Table 14.3.2.1

Individual Listing of Deaths - Safety Analysis Set .................. 197

Table 14.3.2.1.1

Individual Listing of Deaths - Safety Analysis Set - Chinese
Subgroup Analysis .................................................................... 203

Table 14.3.2.1.2

Summary of Deaths - Safety Analysis Set................................ 204

Table 14.3.2.1.2.1

Summary of Deaths - Safety Analysis Set - Chinese
Subgroup Analysis .................................................................... 205

Table 14.3.2.1.3

Notice of Death Listing - Safety Analysis Set .......................... 206

Table 14.3.2.1.3.1

Notice of Death Listing - Safety Analysis Set - Chinese
Subgroup Analysis .................................................................... 211

Table 14.3.2.2

Serious Adverse Events - Safety Analysis Set ......................... 213

Table 14.3.2.2.1.1

Serious Adverse Events - Safety Analysis Set - Chinese
Subgroup Analysis .................................................................... 229

Table 14.3.2.2.2

Summary of Serious Treatment-Emergent Adverse Events by
MedDRA System Organ Class, Preferred Term, andMaximum CTCAE Grade (All Causalities, All Cycles) Safety Analysis Set ................................................................... 234

PFIZER CONFIDENTIAL
Page 10

Page 10

Supplemental Clinical Study Report
Protocol A6181202
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events
Section 14.3.3................................................................................................................. 244
14.4 Dosing, PK, Concomitant and Previous Drug AND Non-Drug Treatments Data
Table 14.4.1

Duration of Treatment - Safety Analysis Set............................ 265

Table 14.4.1.1

Duration of Treatment - Safety Analysis Set - Chinese
Subgroup Analysis .................................................................... 266

Table 14.4.1.2

Dose Administration - Safety Analysis Set .............................. 267

Table 14.4.1.2.1

Dose Administration - Safety Analysis Set - Chinese
Subgroup Analysis .................................................................... 269

Table 14.4.1.3

Cumulative Dose and Relative Dose Intensity - Safety
Analysis Set .............................................................................. 271

Table 14.4.1.3.1

Cumulative Dose and Relative Dose Intensity - Safety
Analysis Set - Chinese Subgroup Analysis .............................. 304

Note: In-text and summary table numbering will not overlap.

PFIZER CONFIDENTIAL
Page 11

Page 11

Supplemental Clinical Study Report
Protocol A6181202
16. APPENDICES
16.1 Study Information
16.1.1 Final Protocol
16.1.4 Investigators and Corresponding Ethics Committees (IEC) or
Institutional Review Boards (IRB), and Curriculum Vitae, (CV)
16.1.4.1 Investigators and Corresponding Ethics Committees(IEC) or Institutional Review Boards (IRB), and Curriculum
Vitae, (CV)
16.1.4.2 Supplemental Report: List of all Centers Within theCountries Participating in the Study
16.1.4.3. Study Administrative Structure: See primary CSR
16.1.5 Signatures of Principal or Coordinating Investigators or Sponsor's
Responsible Medical Officer, Depending on The Regulatory Authority's
Requirement
16.1.5.1 Sponsor
16.1.5.2 CSR Investigator Declaration
16.1.6 Listing of Subjects Receiving Test Drug(s)/Investigational
Product(s) From Specific Batches, Where More Than One Batch Was
Used
16.1.7 Randomization Scheme and Codes (Subject Identification andTreatment Assigned): Not applicable
16.1.9 Documentation of Statistical Methods
16.1.9.1 Statistical Analysis Plan
16.1.9.2 Statistical Output: Not applicable
16.2 Subject Data Listings
16.2.1 Discontinued Subjects
16.2.1.3 Subject Discontinuations from Study - Full Analysis Set
16.2.1.4 Subject Discontinuations from Treatment - Safety
Analysis Set
16.2.1.5 Subjects not meeting the Eligibility Criteria
16.2.2 Protocol Deviations – Full Analysis Set
16.2.4 Demographic Data
16.2.4.1 Demographic Characteristics - Full Analysis Set
16.2.4.2 Primary Diagnoses and Durations - Full Analysis Set
16.2.4.3 Medical History - Full Analysis Set
PFIZER CONFIDENTIAL
Page 12Page 12

Supplemental Clinical Study Report
Protocol A6181202
16.2.4.4 Pregnancy Test by Visit - Full Analysis Set
16.2.5 Compliance and/or Drug Concentration Data
16.2.5.1 Administration Schedule - Safety Analysis Set
16.2.5.1.1

Dose Modification - Safety Analysis Set

16.2.5.1.2

Cumulative Dose and Relative Dose Intensity - Safety
Analysis Set

16.2.5.1.3

Medication Error - Safety Analysis Set

16.2.5.2.1

Treatments Prior to Start of Study Treatment

16.2.5.2.1.1

Prior Systemic Therapies - Full Analysis Set

16.2.5.2.2.2

Prior Surgery for Primary Diagnosis - Full Analysis
Set

16.2.5.2.3

Concomitant Drug Treatments - Safety Analysis Set

16.2.5.2.4

Concomitant Non-drug Treatments - Safety Analysis Set

16.2.5.2.5

Concurrent Somatostatin Therapy - Safety Analysis Set

16.2.5.2.6

Follow-Up Systemic Therapy - Safety Analysis Set

16.2.5.3.6

Listing of Levels of Soluble Protein Biomarker sKIT and
Changes From Baseline (Ratio of Values to Baseline) byVisit (Naïve and Later-Line Cohort) - Soluble Protein
Biomarker Evaluable Population

16.2.6 Individual Efficacy Response Data
16.2.6.1 ECOG Performance Status - Full Analysis Set
16.2.6.2 Tumour Measurements
16.2.6.2.1

Tumor Measurements (Based on the investigatorassessment according to RECIST) - Full Analysis Set

16.2.6.3.1

Tumor Assessments (Based on the investigator assessment
according to RECIST) - Full Analysis Set

16.2.6.5 Overall Survival - Full Analysis Set
16.2.6.8 Chromogranin A response - Full Analysis Set
16.2.7 Adverse Event Listing by Subject
16.2.7.1 Listing of Follow-Up and Death Summary - Safety Analysis Set
16.2.8 Listing of Individual Laboratory Measurements by Subject
16.2.8.1 Laboratory Data
16.2.8.1.1

Laboratory Data - Safety Analysis Set

16.2.8.1.1.1

Laboratory Data: NCI-CTC Grades - Safety
Analysis Set

PFIZER CONFIDENTIAL
Page 13

Page 13

Supplemental Clinical Study Report
Protocol A6181202
16.2.8.1.2

Laboratory Test Abnormalities, by Subject - Safety
Analysis Set

16.2.8.1.3

Laboratory Test Abnormalities, by Test - Safety Analysis
Set

16.2.8.1.4

Other Laboratory Tests - Safety Analysis Set

16.2.8.1.5

Listing of ≥ Grade 3 Hematology Results - Safety Analysis
Set

16.2.8.1.6

Listing of ≥ Grade 3 Chemistry Results - Safety Analysis
Set

16.2.8.2.1

Vital Signs Data - Safety Analysis Set

16.2.8.2.2

Vital Signs Change from Baseline - Safety Analysis Set

16.2.8.2.4

Vital Signs Values in Specific Categories - Safety Analysis
Set

16.2.8.3.1

Electrocardiogram Data - Safety Analysis Set

16.2.8.3.2

ECG Change from Baseline - Safety Analysis Set

16.2.8.4.2

Physical Examination: Changes from Screening - Full
Analysis Set

16.2.8.5.1

EORTC QLQ-C30 Questionnaire Assessments - Full
Analysis Set

16.2.8.5.2

Derived EORTC QLQ-C30 Questionnaire - Full Analysis
Set

16.2.8.5.3

EORTC QLQ - G.I.NET21 (Carcinoid/Neuroendocrine)
Questionnaire Assessments - Full Analysis Set

16.2.8.5.4

Derived EORTC QLQ - G.I.NET21(Carcinoid/Neuroendocrine) Questionnaire - Full Analysis
Set

16.2.8.7 Investigator Comments
16.3 Case Report Forms (CRFs)
All Case Report Forms (CRFs) or Data Collection Tools (DCTs) agreed upon with regulatory
agencies to be submitted will be provided in Module 5 of the Common Technical Document(CTD) for New Drug Applications (United States of America) and in Section 5 of New Drug
Submissions (Canada), and will be available upon request for Marketing Authorization
Applications (Europe) and Japanese New Drug Applications (JNDA).
16.3.1 CRFs For Deaths, Other Serious Adverse Events, and Withdrawals
For Adverse Events: Not applicable
16.3.2 Other CRF’s Submitted: Not applicable
16.4 Individual Subject Data Listings: Not applicable
PFIZER CONFIDENTIAL
Page 14

Page 14

Supplemental Clinical Study Report
Protocol A6181202
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
AE
CDD
CI
CIOMS
CRF
CSR
Ctrough
DCT
ECG
ECOG
EORTC QLQ
FAS
FLT3
FPFV
GCP
HR
ICH
IEC
IRB
Ki-67 index
KIT
LPLV
MedDRAmTOR
NCI CTC
NCI-CTCAE
OS
PDGFR
PFS
PK
pNET
PS
PT
RDI

Definition
Adverse event
Continuous daily dosing
Confidence interval
Council for International Organizations of Medical Sciences
Case report form
Clinical study reportplasma trough concentrations
Data collection tools
Electrocardiogram
Eastern Cooperative Oncology Group
European Organization for Research and Treatment of Cancer Quality ofLife Questionnaire
Full Analysis Set
FMS-like tyrosine kinase 3
First Patient First Visit
Good Clinical PracticeHazard ratio
International Conference on Harmonization
Independent Ethics Committee
Institutional Review Board
A biomarker for assessing the tumor grade
kinase insert domain for tyrosine
Last Patient Last Visit
Medical Dictionary for Regulatory Activities
Mammalian target of rapamycin
National Cancer Institute Common Toxicity Criteria
National Cancer Institute Common Terminology Criteria for Adverse
EventsOverall survival
Platelet-derived growth factor receptor
Progression-free survival
Pharmacokinetic
Pancreatic neuroendocrine tumor
Performance status
Preferred Term
Relative dose intensity
PFIZER CONFIDENTIAL
Page 15

Page 15

Supplemental Clinical Study Report
Protocol A6181202
RECIST
RET
SAE
SAP
SAS
sCSR
SD
sKIT
SOC
TEAE
TSH
VEGF
VEGFR

Response Evaluation Criteria In Solid Tumors
REarranged during Transfection
Serious adverse event
Statistical Analysis Plan
Safety analysis set
Supplemental Clinical Study Report
Standard deviation
Soluble kinase insert domain for tyrosine
System organ classTreatment-emergent adverse event
Thyroid-stimulating hormone
Vascular endothelial growth factor
Vascular endothelial growth factor receptor

PFIZER CONFIDENTIAL
Page 16

Page 16

Supplemental Clinical Study Report
Protocol A6181202
ETHICS
Independent Ethics Committee or Institutional Review Board
The final protocol and any amendments (Section 16.1.1) were reviewed and approved by theInstitutional Review Boards (IRB) and/or Independent Ethics Committees (IEC) at each of
the investigational centers participating in the study. The IRBs and IECs are listed in
Section 16.1.4.
Ethical Conduct of the Study
This study was conducted in compliance with the ethical principles originating in or derived
from the Declaration of Helsinki and in compliance with all International Conference on
Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local
regulatory requirements were followed, in particular, those affording greater protection to thesafety of study participants.
INTRODUCTION
Study A6181202 primary analysis data have been reported previously in the primary clinicalstudy report (CSR) for the global population1 (dated 11 November 2016) and primary CSR
for the China subgroup that comprised of patients enrolled at sites in China2 (dated
09 November 2016). The present supplemental clinical study report (sCSR) presents the
final planned analyses of selected efficacy and safety data for both the study populations up
to the last patient last visit (LPLV), 26 July 2018.
Pancreatic neuroendocrine tumors (pNETs) are rare malignancies with an incidence ofapproximately 2.5 to 5 cases per 100,000 per year. Because of the relatively indolent natureof this disease, the majority of patients are diagnosed with disseminated metastases. For
patients with metastatic disease, the 5-year survival rate is low, and cure is generally notpossible.3
Their indolent nature and resistance to traditional treatment modalities distinguishwell-differentiated neuroendocrine tumors from poorly differentiated carcinoma and small
cell carcinoma. These latter tumors pursue a far more aggressive clinical course, are often
responsive to platinum-based chemotherapy regimens, and are characterized histologically by
the presence of frequent mitoses and areas of necrosis. Because of biological differences
between poorly differentiated carcinoma and well-differentiated pNETs, treatment regimens
and response to treatment for each differ.
At the start of the study, except for surgery for localized disease, there was a lack of available
therapies with meaningful, clinical benefit for well-differentiated pNETs.4 Available
treatment options for unresectable disease have included the use of somatostatin analogs,
which may relieve symptoms related to hormonal hypersecretion, but there is limited
evidence to support a direct antitumor effect in progressive, well-differentiated pNETs. The
palliative benefit of interferon-, combination chemotherapy, radiotherapy, cryotherapy, andchemoembolization therapy have been questioned, given the resistance of these tumors to
traditional treatment modalities and the associated toxicity of many of these treatments.
PFIZER CONFIDENTIAL
Page 17

Page 17

Supplemental Clinical Study Report
Protocol A6181202
Therefore, newer agents with novel mechanisms of action were desperately needed for thetreatment of this disease.
pNETs are highly vascular tumors. Several tumors, including pNETs, aberrantly express
both the vascular endothelial growth factor (VEGF) ligand and its FLK-1/KDR receptor(VEGFR), both of which play critical roles in tumor angiogenesis.5 The expression of VEGF
upregulates intracellular anti-apoptotic proteins, facilitates tumor growth, and is associatedwith relatively short disease free and overall survival. In addition to VEGFR,
platelet-derived growth factor receptor (PDGFR) is also activated by phosphorylation inseveral tumor types and is also involved in tumor neoangiogenesis. Inhibition ofangiogenesis would therefore be expected to result in growth inhibition and regression ofthese tumors. In one study performed in a mouse model, treatment with the angiogenesis
inhibitors angiostatin and endostatin reduced the tumor burden of pNETs by 60%.6
Investigation of angiogenesis inhibitors such as sunitinib in patients with pNETs is thereforeof great interest. Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of kinase
insert domain for tyrosine (KIT), PDGFRs, VEGFRs, REarranged during Transfection (RET)kinase, and FMS-like tyrosine kinase 3 (FLT3). Sunitinib has been evaluated in patients with
pNETs in 2 clinical trials, a pivotal Phase 3 double-blind placebo-controlled study(A6181111) and supportive Phase 2 open label study with a pNET cohort (RTKC 0511 015).
Phase 3 study A6181111 had previously demonstrated a clinically meaningful improvementin progression-free survival (PFS) in subjects with progressive well-differentiated pNETs,
with a median PFS of 11.4 months (95% confidence interval [CI]: 7.4, 19.8) in the sunitinibarm and 5.5 months (95% CI: 3.6, 7.4) in the placebo arm with a hazard ratio (HR) of 0.418(95% CI: 0.263, 0.662) (2-sided p=0.0001).7 Additionally, sunitinib treatment was
associated with longer survival compared with placebo, with a HR for overall survival (OS)of 0.409 (95% CI: 0.187-0.894; p=0.0204; 30 OS events; data cutoff 15 April 2009). OS was
updated 5 years after the last subject first visit (data cutoff of 15 April 2014) and continued toshow a favorable longer survival trend compared to placebo, with a HR of 0.730 (95% CI:
0.504, 1.057; 2-sided p=0.0940). Median OS was 38.6 months (95% CI: 25.6, 56.4) in thesunitinib group and 29.1 months (95% CI: 16.4, 36.8) in the placebo group.8 Although the
OS improvement was confounded by the unblinding of the study and subjects receiving
placebo crossing over to the sunitinib group, the OS still showed a favorable trend towards
sunitinib.
The objectives of the Phase 4 study A6181202 were to confirm the safety and efficacy
findings of the pivotal Phase 3 study A6181111, provide additional information on the study
population, and to meet regulatory post-approval commitments. Study A6181202 met its
primary objective of confirming sunitinib treatment effect on PFS per investigatorassessment in patients with progressive advanced metastatic, well-differentiated, unresectable
pNETs per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.0), with a
median investigator-assessed PFS of 13.2 months (95% CI: 10.9, 16.7). There were no newsafety findings identified in this study compared to those in Study A6181111 or otherprevious sunitinib studies, and the benefit-risk profile of sunitinib was confirmed to befavorable for this patient population.
PFIZER CONFIDENTIAL
Page 18

Page 18

Supplemental Clinical Study Report
Protocol A6181202
STUDY OBJECTIVES
Primary Objective

To confirm sunitinib treatment effect on PFS per investigator assessment in subjects withadvanced/metastatic, well-differentiated, unresectable, pNETs per RECIST 1.0.

Secondary Objectives

To assess PFS per independent radiological review; time-to-tumor-progression, OS,objective response rate; duration of response; and time-to-tumor response;To evaluate the use of Choi criteria and Chromogranin A response; explore the potential
relationship between plasma soluble KIT (sKIT) levels and measures of efficacy
including PFS;

To assess the safety and tolerability of sunitinib;To assess patient-reported outcomes;

To assess sunitinib and its active metabolite, SU12662, plasma trough concentrations(Ctrough) and to potentially explore the relationship between Ctrough and safety, biomarker,
and efficacy.

After completion of the primary analysis of Study A6181202 and confirmation that the
primary study objective was met, patients who were still showing clinical benefit from study
treatment according to the investigator were candidates for continued sunitinib treatment.
The purpose of this sCSR is to provide the final planned analyses of OS data and selectedsafety data collected up to the LPLV, 26 July 2018 for the global population. In addition,
selected data that were separately analyzed for the China subgroup are also presented.
INVESTIGATIONAL PLAN
The primary objective of the A6181202 study was to confirm the safety and efficacy findings
from the pivotal Phase 3 study of sunitinib in patients with progressive advanced metastatic
well-differentiated, unresectable pNETs, Study A6181111. The study was conducted toprovide additional information in this population and meet regulatory post-approvalcommitments.
Eligible patients were enrolled to receive sunitinib orally at 37.5 mg once a day on acontinuous daily dosing (CDD) schedule. Patients continued treatment until theyexperienced death or unacceptable toxicity, withdrew consent, met other withdrawal criteria,
or until the final analysis for the study was performed. Patients with evidence of diseaseprogression could continue treatment if judged to have clinical benefit.
After discontinuation of treatment and the mandated 28-day follow-up, patients were
followed-up to collect information on survival and further antineoplastic therapy.

PFIZER CONFIDENTIAL
Page 19

Page 19

Supplemental Clinical Study Report
Protocol A6181202
The primary analysis period of the study was from the first patient first visit (FPFV) on
06 June 2012 until the data cutoff on 19 March 2016. As the majority of patients were infollow-up at the time of data cutoff, the OS data were not mature at the time. An updated
analysis of OS is reported in the present sCSR. In addition, summaries of the planned safety
data collected up to LPLV, 26 July 2018, are also provided.
Study Design
A6181202 was a single arm, multinational, multi-center, open label, Phase 4 clinical study
evaluating the efficacy and safety of sunitinib in patients with progressive, advanced
metastatic well-differentiated, unresectable pNETs.1,2All enrolled patients received the same treatment with sunitinib. After treatment
discontinuation there was a mandated 28-day follow-up, followed by a long-term follow-up
to collect information on patient survival and selected safety measures.
Enrolled patients were divided into 2 cohorts:


Treatment-naïve cohort comprising of patients who had not received any previous
systemic therapies (ie, first-line systemic), including chemotherapy, immunotherapy,
intravenous peptide receptor radiotherapy, or investigational anticancer agent other thansomatostatin analogs;



Later-line cohort comprising of patients who had experienced progressive disease on orafter prior systemic therapy.

Selection of Study Population
Inclusion and Exclusion Criteria
Following primary analysis, patients who were clinically benefiting from study treatment as
judged by the investigator continued study treatment and follow-up.
Patients had to meet the eligibility criteria to participate in this study. Eligibility criteria weresimilar to those established for the previous study, A6181111.7 A detailed list of theselection criteria is provided in the primary CSRs,1,2 and an abbreviated list is presented
below.
Inclusion criteria included:
1. Histologically or cytologically proven diagnosis of well-differentiated pNETs(according to World Health Organization 2000 classification)9 with available
Ki-67 (biomarker for assessing the tumor goals) index.
2. Unresectable (as assessed by the investigator) or metastatic disease documented on ascan (computed tomography, magnetic resonance imaging, or Octreoscan) taken
within 28 days of study enrollment. Disease progression (per RECIST 1.0) within
12 months prior to study enrollment.
PFIZER CONFIDENTIAL
Page 20

Page 20

Supplemental Clinical Study Report
Protocol A6181202
3. Disease that was not amenable to surgery, radiation, or combined modality therapy
with curative intent.
4. Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 0 or 1.
5. Life expectancy 3 months.
Exclusion criteria included:
1. Prior treatment with any tyrosine kinase inhibitors, anti-VEGF angiogenesis
inhibitors, non-VEGF targeted angiogenesis inhibitors, or mammalian target of
rapamycin (mTOR) inhibitors.
2. Diagnosis of any second malignancy within the last 5 years, except for adequately
treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix
uteri.
3. Abnormal cardiac function with abnormal 12-lead electrocardiogram (ECG).
Ongoing Grade ≥2 cardiac dysrhythmias by National Cancer Institute Common
Toxicity Criteria (NCI CTC version 3.0), atrial fibrillation of any grade, or
prolongation of the QTc interval to >450 msec for males or >470 msec for females.
4. Symptomatic brain metastases, spinal cord compression, or new evidence of brain or
leptomeningeal disease.
5. Left ventricular ejection fraction 50% as measured by either multigated acquisition
scan or echocardiogram.
Treatments
Sunitinib was available as an oral drug formulation as 30 hard gelatin capsules of the doses
12.5 mg or 25 mg equivalents of sunitinib free base.
Eligible patients were enrolled to receive sunitinib orally at 37.5 mg once a day on a CDD
regimen. Dose escalation to 50 mg daily was allowed after the first 8 weeks of treatment forpatients not experiencing a complete response or partial response according to RECIST 1.0,
provided their treatment-related non-hematological or hematological adverse events (AEs), if
any, were Grade ≤1 or Grade ≤2, respectively. For patients experiencing severe toxicity, thedose of 37.5 mg could be reduced to 25 mg daily, which is the minimum dose acceptable fordaily dosing of sunitinib. Intra-patient re-escalation of study drug back to previous dose waspermitted at the discretion of the investigator and considering the patient’s clinical status.
Efficacy, Pharmacokinetic, and Safety
Efficacy Evaluations
The primary efficacy analysis was for PFS, defined as the time from the date of enrollment to
the first objective progressive disease or death due to any cause, whichever occurred first.
The primary efficacy endpoint results were summarized in the primary CSR, dated
PFIZER CONFIDENTIAL
Page 21

Page 21

Supplemental Clinical Study Report
Protocol A6181202
11 November 2016.1 An updated analysis of the OS is reported in the present sCSR. OS was
defined as the time from date of enrollment to date of death due to any cause as described in
the Statistical Analysis Plan (SAP; Section 16.1.9.1).
Safety Evaluations
Safety evaluations were based on assessment of AEs (type, incidence, severity [graded by
National Cancer Institute Common Terminology Criteria for Adverse Events {NCICTCAE}, version 3.0, dated August 9, 2006], seriousness, and relatedness), serious adverse
events (SAEs), and laboratory safety (hematology, blood chemistry, urinalysis, and liverfunction). Medical Dictionary for Regulatory Activities (MedDRA) version 21 coding wasapplied.
Pharmacokinetic Evaluations
No pharmacokinetic (PK) evaluations were planned after the completion of the primary
analysis. Updated patient listings for PK data are provided in the present sCSR.
Statistical Methods Planned in the Protocol
Time to event endpoints were summarized using the Kaplan-Meier method and displayed
graphically when appropriate. Median event times and 2-sided 95% CI for each median were
provided.
Descriptive statistics, including the mean, standard deviation (SD), median, minimum, andmaximum values, were provided for continuous data.
The number and percentage of patients in each category were provided for categoricalvariables.
For the OS analysis in this report, data from the treatment-naïve cohort of the global
population were combined with data from the treatment-naïve patients in theintention-to-treat population from Study A6181111.
Further details on statistical methods are provided in the SAP (Section 16.1.9.1).
Data Sets Analyzed
The following analysis populations were defined for the global population and China
subgroup. The China subgroup analyses sets were a subset of the corresponding global
population analyses sets.
Full Analysis Set (FAS) included all patients who were enrolled into the study regardless ofwhether patients received study drug or not. The FAS was the analysis population forevaluating patient characteristics and efficacy endpoints.
Safety Analysis Set (SAS) included all patients who received at least 1 dose of study drug.
The SAS population was the analysis population for evaluating treatment administration andcompliance, and safety.
PFIZER CONFIDENTIAL
Page 22

Page 22

Supplemental Clinical Study Report
Protocol A6181202
Changes in the Conduct of the Study
There were 3 amendments to the clinical study protocol as follows.
Protocol Amendment 1, dated 31 July 2012
The following changes were made.


Updated medication errors language;Updated AE reporting language;



Minor administrative changes.

Protocol Amendment 2, dated 25 January 2013
The following changes were made.


Updated AE reporting language;Included changes only applicable to Japan (eg, central laboratory for Chromogranin A
assessment, inclusion age for Japan ≥20);

Clarified usage of validated analytical methods in PK analyses.

Protocol Amendment 3, dated 05 July 2016
The following changes were made after the data cutoff point for the primary analysis,
19 March 2016.


Reduced the number of efficacy assessments after collection of data for the primary andmost secondary endpoints;



Minor administrative changes and updates to the safety reporting language.

The most recent version of the protocol including all amendments is provided in
Section 16.1.1.
Changes in the Planned Analysis
The SAP applicable to the global population was amended twice.
SAP version 2 that was approved on 14 September 2015 provided detailed description of
biomarker data analysis.
SAP version 3 that was approved on 3 December 2015 removed unnecessary supportive
analyses and provided additional clarifications on populations for each analysis. The
applicable SAP for the China subgroup analyses is version 1.0, dated 25 January 2016.2
SAP version 3 and China subgroup SAP are provided in Section 16.1.9.1.
PFIZER CONFIDENTIAL
Page 23

Page 23

Supplemental Clinical Study Report
Protocol A6181202
RESULTS
Results of data analyzed up to the data cutoff date of the primary analyses were reported
previously in the primary CSRs for the global population,1 dated 11 November 2016 and for
the China subgroup,2 dated 09 November 2016. Analyses of OS and the planned safety datacollected up to the LPLV, 26 July 2018, are presented in this sCSR.
The China subgroup is a subset of the global population. Some efficacy and safety analyses
were performed separately for the China subgroup (Section 14), while patient listings(Section 16) for this subgroup are part of the listings of the global population.
Patient Disposition
In the global population, a total of 106 patients were enrolled and treated with sunitinib. Of
these, 61 patients were in the treatment-naïve cohort and 45 patients in the later-line cohort.
Patient discontinuations from the study and treatment phases are presented in Table 1. At thedata cutoff date of the primary CSR (19 March 2016), a total of 68 (64.2%) patients wereongoing, either on-treatment or in long-term survival follow-up.1 At the LPLV, of the
106 enrolled patients, 47 (44.3%) patients discontinued from the study due to death and theremaining 59 (55.7%) patients discontinued due to loss to follow-up (10 [9.4%] patients),
refusal for continued follow-up (4 [3.8%] patients) or for other reasons including end of thestudy by the sponsor (45 [42.5%] patients). Death was reported as the reason for study
discontinuation in a smaller proportion of patients in the treatment-naïve cohort (19 [31.1%]
patients) than in the later-line cohort (28 [62.2%] patients).
During the treatment phase, discontinuation due to objective progression or relapse wasreported in 64 (60.4%) patients overall, with similar proportions in the treatment-naïve andlater-line cohorts (36 [59.0%] patients and 28 [62.2%] patients, respectively). Treatment
discontinuation due to death was reported in 1 patient each in the treatment-naïve cohort(1.6%) and the later-line cohort (2.2%). Treatment discontinuation due to study drug-relatedAE(s) were reported in 11 (10.4%) patients overall, with similar proportions in thetreatment-naïve (9.8%) and later-line (11.1%) cohorts. Overall, 5 (4.7%) patients
discontinued treatment due to global deterioration of health status.

PFIZER CONFIDENTIAL
Page 24

Page 24

Supplemental Clinical Study Report
Protocol A6181202
Table 1.

Discontinuations from Study Phase (Full Analysis Set) and Treatment Phase(Safety Analysis Set): Global Population

Screened = 123

Treatment-Naïve
CohortN = 61n (%)

Later-Line
CohortN = 45n (%)

Total
N = 10619 (31.1)

28 (62.2)

47 (44.3)

Relation to study drug not defined
Lost to follow-up
OtheraPatient refused further follow-up

42 (68.9)
8 (13.1)
30 (49.2)
4 (6.6)

17 (37.8)
2 (4.4)15 (33.3)
059 (55.7)
10 (9.4)
45 (42.5)
4 (3.8)Total

61 (100.0)

45 (100.0)

106 (100.0)

1 (1.6)

1 (2.2)2 (1.9)Relation to study drug not defined
Global deterioration of health status
Objective progression or relapse
Other
Patient refused continued treatment forreason other than adverse event

52 (85.2)
3 (4.9)36 (59.0)
8 (13.1)
5 (8.2)36 (80.0)
2 (4.4)28 (62.2)
5 (11.1)
1 (2.2)88 (83.0)
5 (4.7)64 (60.4)
13 (12.3)
6 (5.7)Adverse event related to study drug

6 (9.8)5 (11.1)

11 (10.4)

Adverse event not related to study drug

2 (3.3)3 (6.7)5 (4.7)61 (100.0)

45 (100.0)

106 (100.0)

Discontinuations from Study Phase
Patient died

Discontinuations from Treatment Phase
Patient died

Total

n (%)

Sources: Table 14.1.1.3 and Table 14.1.1.4
aIncludes discontinuation due to end of study.
Percentage is based on the number of enrolled patients in each cohort.
Abbreviations: N = number of patients enrolled; n = number of patients who met the criteria.

The China subgroup comprised of 31 patients enrolled in China and treated with sunitinib.
At the data cutoff date of the primary CSR (19 March 2016),2 26 (83.9%) patients wereongoing, either on-treatment or in long-term survival follow-up. Patient discontinuations
from the study and treatment phase are presented in Table 2. At the LPLV, of the 31 enrolled
patients, 9 (29.0%) patients discontinued from the study due to death, and the remaining
22 (71.0%) patients discontinued due to loss to follow-up (2 [6.5%] patients) or for otherreasons including end of the study by the sponsor (20 [64.5%] patients).
During the treatment period, discontinuation because of objective progression or relapse wasreported in 21 (67.7%) patients and due to death in 1 patient (3.2%). Overall, treatment
discontinuation due to AE(s) related to the study drug were reported in 2 (6.5%) patients.
PFIZER CONFIDENTIAL
Page 25

Page 25

Supplemental Clinical Study Report
Protocol A6181202
Table 2.

Discontinuations from Study Phase (Full Analysis Set) and Treatment Phase(Safety Analysis Set): China Subgroup

Assigned to Study Treatment

Total
N = 31n (%)

Discontinuations from Study Phase
Patient died

9 (29.0)

Relation to study drug not defined
Lost to follow-up
Othera22 (71.0)
2 (6.5)20 (64.5)

Total

31 (100.0)

Discontinued from Treatment Phase
Patient died1 (3.2)

Relation to study drug not defined
Objective progression or relapse
Other
Patient refused continued treatment for reason other than adverseevent

26 (83.9)
21 (67.7)
2 (6.5)3 (9.7)Adverse event related to study drug

2 (6.5)Adverse event not related to study drug

2 (6.5)Total

31 (100.0)

Sources: Table 14.1.1.3.1 and Table 14.1.1.4.1
aIncludes discontinuation due to end of study.
Percentage is based on the enrolled number of patients.
Abbreviations: N = number of patients enrolled; n = number of patients who met the criteria.

By patient listings for discontinuation from the study or treatment are provided inTables 16.2.1.3 and 16.2.1.4, respectively; and patients not meeting the eligibility criteria arelisted in 16.2.1.5.
Demography
Demographic characteristics were described in the primary CSRs for the global population
and China subgroup.1,2
Briefly, in the global population, the overall FAS population was comprised of 63 (59.4%)
male and 43 (40.6%) female patients. The majority of the demographic and baselinecharacteristics were similar between the 2 cohorts; however, the proportion of female andAsian patients was comparatively lower in the later-line cohort. All patients had an ECOG
PS of either 0 (64.2%) or 1 (35.8%) at baseline with no notable differences between the
2 cohorts.
PFIZER CONFIDENTIAL
Page 26

Page 26

Supplemental Clinical Study Report
Protocol A6181202
In the China subgroup, the overall FAS population was comprised of 31 patients,
19 (61.3%) male and 12 (38.7%) female patients. All patients had an ECOG PS of either 0(58.1%) or 1 (41.9%) at baseline.
By patient listings are provided for demographic characteristics in Table 16.2.4.1, primary
diagnoses and durations in Table 16.2.4.2, medical history in Table 16.2.4.3, and pregnancy
test results by visit in Table 16.2.4.4.
Protocol Deviations
Section 16.2.2 lists the protocol deviations recorded for this study after the primary CSR data
cutoff date, 19 March 2016. Overall, of the 181 protocol deviations recorded, 10 wereconsidered as major protocol deviations. The majority of the minor protocol deviations wererelated to study procedures or tests not done. Of the 10 major protocol deviations, 4 wererelated to study procedures or tests not done, 3 to AEs or SAEs, 2 to signing of informed
consent form, and 1 to administration of the study drug.
None of the protocol deviations was considered to significantly impact patient safety or theinterpretation of study results.
A formal acknowledgment by the study team was made that deviations were reviewed and
GCP compliance was maintained.
Prior and Concomitant Treatments
Prior and concomitant treatments were described in the primary CSRs for the global
population and the Chinese subgroup.1,2
Updated patient listings are provided for prior systemic therapies in Table 16.2.5.2.1.1, priorsurgery in Table 16.2.5.2.2.2, concomitant drug treatments in Table 16.2.5.2.3, concomitant
nondrug treatments in Table 16.2.5.2.4, concurrent somatostatin therapy in Table 16.2.5.2.5,
and follow-up systemic therapy in Table 16.2.5.2.6.
Efficacy Results
Overall Survival: Global Population
For the global population, the overall OS data for the FAS up to the LPLV, 26 July 2018,
were analyzed. The overall OS data for the treatment-naïve and later-line cohorts arepresented in Table 3 and Figure 1. At the end of the study, 20 (32.8%) patients in thetreatment-naïve cohort and 28 (62.2%) patients in the later-line cohort died, primarily due todisease under study. A total of 58 (54.7%) patients were censored, of which
50 (47.2%) patients were lost to follow-up (includes patients who were alive at the time thestudy was ended by the sponsor). A higher proportion of the patients were censored in thetreatment-naïve cohort (41 [67.2%] patients) than in the later-line cohort(17 [37.8%] patients).
Overall, the median OS for the global population was estimated to be 54.1 months(95% CI: 37.9, not reached). The median OS could not be determined for thetreatment-naïve cohort; and was 37.9 months (95% CI: 22.9, 56.1) for the later-line cohort.
PFIZER CONFIDENTIAL
Page 27

Page 27

Supplemental Clinical Study Report
Protocol A6181202
Survival probability at Year 1 was 88.3% (95% CI: 80.3, 93.2) for the total population:
91.5% (95% CI: 80.9, 96.4) for the treatment-naïve cohort and 84.3% (95% CI: 69.8, 92.2)
for the later-line cohort; and at Year 2 was 75.0% (95% CI: 65.3, 82.4) for the total
population: 84.4% (95% CI: 72.2, 91.6) for the treatment-naïve cohort and 63.0% (95% CI:
46.8, 75.5) for the later-line cohort.
Table 3.

Overall Survival – Full Analysis Set; Global Population
Treatment-Naïve
CohortN = 61

Later-Line
CohortN = 45Total
N = 106

Number of deaths, n (%)aCause of death, n (%)
Disease under study
Study treatment toxicity
UnknownOther

20 (32.8)

28 (62.2)

48 (45.3)

16 (26.2)
02 (3.3)2 (3.3)26 (57.8)
00
2 (4.4)42 (39.6)
02 (1.9)4 (3.8)

Number censored, n (%)
Reason for censorship, n (%)
Patient withdrew consent for additional
follow-up
Lost to follow-up or alive when study endedb

41 (67.2)

17 (37.8)

58 (54.7)

4 (6.6)4 (8.9)8 (7.5)37 (60.7)

13 (28.9)50 (47.2)

Survival probability at Year 1c (95% CI)d, %Survival probability at Year 2c (95% CI)d, %91.5 (80.9, 96.4)
84.4 (72.2, 91.6)

84.3 (69.8, 92.2)
63.0 (46.8, 75.5)

88.3 (80.3, 93.2)
75.0 (65.3, 82.4)

Kaplan-Meier estimates of time to event (months)
quartiles (95% CIe)
25%
50%
75%

30.0 (20.3, 41.7)- (41.7, -)-16.4 (8.4, 26.3)
37.9 (22.9, 56.1)
59.3 (46.9, -)23.4 (17.5, 30.0)
54.1 (37.9, -)- (59.3, -)Sources: Tables 14.2.6.2 and 14.2.6.3
A patient could have more than 1 cause of death.
a
Investigator was notified of death of 1 patient enrolled in China in the treatment-naïve cohort after the patient
discontinued from study.
bIncludes patients who were alive at the last survival follow-up visit.
c
Estimated from Kaplan-Meier curve.
dCalculated from the log [-log (1 or 2-year survival probability)] using a normal approximation and backtransformation.
e
Calculated from Brookmeyer and Crowley Method.
Abbreviations: CI = confidence interval, N = number of patients enrolled; n = number of patients who met thecriteria.

PFIZER CONFIDENTIAL
Page 28

Page 28

Supplemental Clinical Study Report
Protocol A6181202
Figure 1. Overall Survival – Treatment-Naïve Cohort and Later-Line Cohort - Full
Analysis Set; Global Population

Source: Figure 14.2.5.2

For the global population, a combined analysis was done to compare treatment-naïve
sunitinib-treated patients pooled from 2 studies, A6181202 and A6181111 (sunitinib arm),with placebo-treated patients from A6181111 study (placebo arm) (Table 4 and Figure 2). A
total of 22 (21.6%) patients in the sunitinib arm and 6 (17.1%) patients in the placebo arm
died, mostly due to the disease under study. A high proportion of the patients were censoredin the 2 arms: 80 (78.4%) and 29 (82.9%) patients, respectively, either because the patientswere in long-term survival follow-up at the data cutoff date in Study A6181111 (38 [37.3%]
and 28 [80.0%] patients, respectively) or were alive when Study A6181202 ended or werelost to follow-up (37 [36.3%] patients and 1 [2.9%] patient, respectively) or refused
follow-up (5 [4.9%] patients and none, respectively).
The median OS could not be determined for either arm. Survival probability at Year 1 was
92.0% (95% CI: 83.8, 96.1) for the sunitinib arm and 86.3% (95% CI: 67.4, 94.7) for theplacebo arm; and at Year 2 was 85.1% (95% CI: 74.2, 91.6) for the sunitinib arm and could
not be determined for placebo arm. The estimated HR was 0.303 (95% CI: 0.100, 0.921),
indicating a 69.7% reduction in the risk of death with sunitinib treatment compared withplacebo; and the difference was statistically significant (p-value = 0.013).
It should be noted that survival follow-up was shorter in Study A6181111 (data cutoff date,
15 April 2009; range for survival follow-up: 0.03 to 20.63 months)7 compared withPFIZER CONFIDENTIAL
Page 29

Page 29

Supplemental Clinical Study Report
Protocol A6181202
Study A6181202 (data cutoff date, 26 July 2018; range of survival follow-up, 0.03 to
70.83 months; Table 16.2.6.5) leading to an imbalance in the follow-up between sunitinib
and placebo arms.

PFIZER CONFIDENTIAL
Page 30

Page 30

Supplemental Clinical Study Report
Protocol A6181202
Table 4.

Overall Survival – Treatment-Naïve Cohort in Study A6181202 + Sunitinib
Arm Treatment-Naïve Cohort in Study A6181111 versus Placebo Arm
Treatment-Naïve Cohort in Study A6181111 – Full Analysis Set; Global
Population
Sunitinib Arm
N = 102

Placebo Arm
N = 35

Number of deaths, n (%)a22 (21.6)

6 (17.1)

Cause of death, n (%)
Disease under study
Study treatment toxicity
UnknownOther

17 (16.7)
02 (2.0)3 (2.9)4 (11.4)
00
2 (5.7)

Number censored, n (%)

80 (78.4)

29 (82.9)

Reason for censorship, n (%)
In follow-up as of data cutoff in Study A6181111
Patient withdrew consent for additional follow-up
Lost to follow-up or alive when study endedb

38 (37.3)
5 (4.9)37 (36.3)

28 (80.0)01 (2.9)Survival probability at Year 1c (95% CI)d, %Survival probability at Year 2c (95% CI)d, %92.0 (83.8, 96.1)
85.1 (74.2, 91.6)

86.3 (67.4, 94.7)-

Kaplan-Meier estimates of OS (month)
Quartiles (95% CIe)
25%
50%
75%

32.6 (20.6, 58.4)- (41.7, -)-15.5 (5.7, -)- (13.7, -)- (15.5, -)Versus placebo arm naïve cohort in Study A6181111
HRf
95% CI of HR
p-valueg

0.303
0.100, 0.921
0.013

Source: Table 14.2.6.1
aInvestigator was notified of death of 1 patient enrolled in China in the treatment-naïve cohort after the patient
discontinued from study.
bIncludes patients who were alive at the last survival follow-up visit.
c
Estimated from Kaplan-Meier curve.
dCalculated from the log [-log (1 or 2-year survival probability)] using a normal approximation and backtransformation.
e
Calculated from Brookmeyer and Crowley Method.
fBased on the Cox Proportional hazards model.
gOne-sided p-value from the log-rank test.
Abbreviations: CI = confidence interval, HR = hazard ratio; N = number of patients enrolled; n = number ofpatients who met the criteria; OS = overall survival.

PFIZER CONFIDENTIAL
Page 31

Page 31

Supplemental Clinical Study Report
Protocol A6181202
Figure 2. Overall Survival – Treatment-Naïve Cohort in Study A6181202 + Sunitinib
Arm Treatment-Naïve Cohort in Study A6181111 versus Placebo Arm
Treatment-Naïve Cohort in Study A6181111 - Full Analysis Set

Source: Figure 14.2.5.1

Overall Survival: China Subgroup
For the China subgroup, the overall OS data for the FAS at the data cutoff date of this report,
26 July 2018, are presented in Table 5 and Figure 3. Overall, 10 (32.3%) patients died,mostly due to disease under study (6 [19.4%] patients). A high proportion of the patientswere censored (21 [67.7%] patients), primarily because the patients were alive when the
study ended or were lost to follow-up (18 [58.1%] patients).
The median OS could not be determined. Survival probability at Year 1 was 84.1% (95% CI:
66.0, 93.1) and at Year 2 was 77.7% (95% CI: 58.7, 88.7). These estimates were comparablewith survival probability estimates for the overall global population at Year 1 and Year 2:
88.3% (95% CI: 80.3, 93.2) and 75.0% (95% CI: 65.3, 82.4), respectively (Table 3).

PFIZER CONFIDENTIAL
Page 32

Page 32

Supplemental Clinical Study Report
Protocol A6181202
Table 5.

Overall Survival – Full Analysis Set; China Subgroup
Sunitinib
N = 31

Number of deaths, n (%)aCause of death, n (%)
Disease under study
Study treatment toxicity
UnknownOther

10 (32.3)

Number censored, n (%)

21 (67.7)

Reason for censorship, n (%)
Patient withdrew consent for additional follow-up
Lost to follow-up or alive when study endedb

3 (9.7)18 (58.1)

6 (19.4)
01 (3.2)3 (9.7)

Survival probability at Year 1c (95% CI)d, %Survival probability at Year 2c (95% CI)d, %84.1 (66.0, 93.1)
77.7 (58.7, 88.7)

Kaplan-Meier estimates of time to event (month)
Quartiles [95% CIe]
25%
50%
75%

28.8 (5.0, -)- (36.8, -)-Source: Table 14.2.3.1.1
A patient could have more than 1 cause of death.
a
Investigator was notified of death of 1 patient enrolled in China in the treatment-naïve cohort after the patient
discontinued from study.
bIncludes patients who were alive at the last survival follow-up visit.
c
Estimated from the Kaplan-Meier curve.
dCalculated from the log [-log (1 or 2-year survival probability)] using a normal approximation and backtransformation.
e
Calculated from Brookmeyer and Crowley Method.
Abbreviations: CI = confidence interval, HR = hazard ratio; N = number of patients enrolled; n = number ofpatients who met the criteria; OS = overall survival.

PFIZER CONFIDENTIAL
Page 33

Page 33

Supplemental Clinical Study Report
Protocol A6181202
Figure 3. Overall Survival – Treatment-Naïve Cohort versus Later-Line Cohort – Full
Analysis Set; China Subgroup

Source: Figure 14.2.2.1.1

Pharmacokinetic, Pharmacodynamic and Other Results
Listing of patients with PK/pharmacodynamic data were provided for the global populationin the primary CSR.1 Updated listing of patients with data on levels of protein biomarker
sKIT changes from baseline is provided in Table 16.2.5.3.6.
Updated patient listing for Chromogranin A response is provided in Table 16.2.6.8.
Updated patient listing for analyses of patient-reported outcomes is provided for European
Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTCQLQ-C30) assessments in Table 16.2.8.5.1, derived EORTC QLQ-C30 questionnaire in
Table 16.2.8.5.2, EORTC QLQ - G.I.NET21 (Carcinoid/Neuroendocrine) questionnaire
assessments in Table 16.2.8.5.3, and derived EORTC QLQ - G.I.NET21(Carcinoid/Neuroendocrine) questionnaire in Table 16.2.8.5.4.
Safety Results
Extent of Exposure
The global population SAS comprised of 106 patients, all of whom had received at least
1 dose of the study drug. Most patients (90 [84.9%] patients) received treatment for
PFIZER CONFIDENTIAL
Page 34

Page 34

Supplemental Clinical Study Report
Protocol A6181202≥91 days, with a median duration of treatment of 364.0 days (Table 6). The mediantreatment duration was longer in the treatment-naïve cohort (394.0 days) than in the later-line
cohort (311.0 days).
Table 6.

Duration of Treatment – Safety Analysis Set; Global Population

Duration category (days)
1
2-7
8-14
15-28
29-60
61-90
≥91
Median duration (days)
Range (days)

Treatment-Naïve
CohortN = 61

Later-Line Cohort
N = 45Total
N = 106

0
1
0
0
5
3
52
394.0
7 - 1939

0
0
1
0
4
2
38
311.0
14 - 1806

0
1
1
0
9
5
90
364.0
7 - 1939

Source: Table 14.4.1
Duration of treatment is the time period starting from the date of first dose and ending at the last dose.
Abbreviation: N = number of patients with at least 1 dose of study drug.

In this study, patients followed a CDD treatment regimen. For purposes of analysis, a cycle
was defined 28-days. For the global population, dose administration data are summarized inTable 7. Patients received between 1 and 64 cycles, with a median of 13 cycles. Of the73 events of dose reduction, 56 events were in the treatment-naïve cohort and 17 events inthe later-line cohort. Overall, 51 (48.1%) patients had dose reductions, of which, themajority had 1 dose reduced (47 [44.3%] patients) and 4 (3.8%) patients had ≥2 doses
reduced. Of the 557 events of dose interruptions, 360 events were in the treatment-naïve
cohort and 197 events in the later-line cohort. Overall, 84 (79.2%) patients had doseinterruptions, of which 73 (68.9%) patients had a dose interruption due to an AE(treatment-naïve cohort: 46 [75.4%] patients; later-line cohort: 27 [60.0%] patients). Overall,
20 (18.9%) patients had at least 1 dose increase.

PFIZER CONFIDENTIAL
Page 35

Page 35

Supplemental Clinical Study Report
Protocol A6181202
Table 7.

Summary of Dose Administration – Safety Analysis Set; Global Population
Treatment-Naïve
CohortN = 61

Later-Line
CohortN = 45Total
N = 106

Total number of cycles
Median (Range) of cycles administered1011
15 (1 – 60)

762
11 (1 – 64)

1773
13 (1 – 64)

Patients with cycles administered, n (%):
1 cycle2 cycles3 cycles4 cycles5 cycles6 cycles7 cycles8 cycles10 cycles
11 cycles
12 cycles
13 cycles
14 cycles
15 cycles
16 cycles
17 cycles
18 cycles

2 (3.3)3 (4.9)4 (6.6)4 (6.6)5 (8.2)5 (8.2)
1 (1.6)2 (3.3)00
1 (1.6)2 (3.3)
1 (1.6)2 (3.3)4 (6.6)0
3 (4.9)1 (2.2)3 (6.7)2 (4.4)4 (8.9)4 (8.9)2 (4.4)3 (6.7)
1 (2.2)1 (2.2)2 (4.4)1 (2.2)1 (2.2)2 (4.4)1 (2.2)0
1 (2.2)0

3 (2.8)6 (5.7)6 (5.7)8 (7.5)9 (8.5)7 (6.6)4 (3.8)3 (2.8)1 (0.9)2 (1.9)2 (1.9)3 (2.8)3 (2.8)3 (2.8)4 (3.8)1 (0.9)3 (2.8)

Patients with dose reductions, n (%)
Patients with 1 dose reduction, n (%)
Patients with 2 dose reductions, n (%)
Total number of dose reductions

34 (55.7)
30 (49.2)
4 (6.6)56

17 (37.8)
17 (37.8)
0
17

51 (48.1)
47 (44.3)
4 (3.8)73

Patients with dose increase, n (%)
Patients with 1 dose increase, n (%)
Patients with 2 dose increase, n (%)
Total number of dose increase

11 (18.0)
7 (11.5)
4 (6.6)31

9 (20.0)
9 (20.0)0920 (18.9)
16 (15.1)
4 (3.8)40

Patients with dose interruptions, n (%)
Total number of dose interruptions

51 (83.6)
360

33 (73.3)
197

84 (79.2)
557

Reason for dose interruptions, n (%)
Adverse Event(s)Not reported
Other

46 (75.4)
1 (1.6)29 (47.5)

27 (60.0)023 (51.1)

73 (68.9)
1 (0.9)52 (49.1)

PFIZER CONFIDENTIAL
Page 36

Page 36

Supplemental Clinical Study Report
Protocol A6181202
Source: Table 14.4.1.2
If there were no patients receiving a particular number of cycles, this was not displayed in the table.
Patient can contribute to more than one reason.
Patients are counted only once for each reason. Per protocol the patients were enrolled to receive drug
treatment at 37.5 mg once a day.
If a patient receives treatment dose greater than the last dose received, then it is considered as dose increase.
If a patient receives treatment dose less than the last dose received, then it is considered as dose reduction.
Abbreviation: N = number of patients with at least 1 dose of study drug; n = number of patients who met thecriteria.

For the global population, overall cumulative dose and relative dose intensity (RDI) aresummarized in Table 8. The overall median RDI was 92.5% with a lower RDI in thetreatment-naïve (86.9%) than the later-line (97.4%) cohort. The median average daily dose
administered was 34.7 mg.
Table 8.

Overall Cumulative Dose and Relative Dose Intensity – Safety Analysis Set;
Global Population

Actual cumulative dose (mg)Median
Mean
SD
Range
Relative dose intensity (%)
Median
Mean
SD
Range
Average daily dose as administered (mg)Median
Mean
SD
Range

Treatment-Naïve
CohortN = 61

Later-Line Cohort
N = 45Total
N = 106

11712.5
14442.813510.79
187.5 - 70687.5

10237.5
16370.8
16307.51
525.0 - 67200.010912.5
15261.3
14719.56
187.5 - 70687.5

86.9
83.7
19.57
34.2 - 129.6

97.4
91.1
20.74
47.3 - 130.9

92.5
86.8
20.31
34.2 - 130.9

32.6
31.4
7.34
12.8 - 48.6

36.5
34.1
7.78
17.7 - 49.1

34.7
32.6
7.62
12.8 - 49.1

Source: Table 14.4.1.3
Actual Cumulative Dose is actual total dose taken in the cycle.
Actual Dose Intensity is actual total dose taken in the cycle divided by actual number of days in the cycle
including delays.
Relative Dose Intensity is % of Actual to Intended Dose Intensities.
Average Daily Dose is actual total dose taken divided by actual number of days in the study including delays.
Abbreviations: N = number of patients with at least 1 dose of study drug; SD = standard deviation.

The China subgroup SAS comprised of 31 patients, all of whom had received at least 1 doseof the study drug. The majority of patients (27 [87.1%] patients) received study drug for≥91 days, and the median treatment duration was 329 days (Table 9).

PFIZER CONFIDENTIAL
Page 37

Page 37

Supplemental Clinical Study Report
Protocol A6181202
Table 9.

Duration of Treatment – Safety Analysis Set; China Subgroup
Total
N = 31

Duration category (days)
1
2-7
8-14
15-28
29-60
61-90
≥91
Median duration (days)
Range (days)

0
0
0
0
4
0
27
329.0
29 - 1268

Source: Table 14.4.1.1
Duration of treatment is the time period starting from the date of first dose and ending at the last dose.
Abbreviation: N = number of patients with at least 1 dose of study drug.

In the China subgroup, patients received between 1 and 39 cycles, with a median of 12 cycles(Table 10). Overall, 13 (41.9%) patients had dose reductions, of which, the majority ofpatients had 1 dose reduction (10 [32.3%] patients) and 3 (9.7%) patients had 2 or more dose
reductions. Of the 24 (77.4%) patients who had dose interruptions, the majority had the doseinterruption due to an AE (21 [67.7%] patients), similar to the global cohort (68.9%)(Table 7). Overall 5 (16.1%) patients had at least 1 dose increase.

PFIZER CONFIDENTIAL
Page 38

Page 38

Supplemental Clinical Study Report
Protocol A6181202
Table 10. Summary of Dose Administration – Safety Analysis Set; China Subgroup
Total
N = 31
Total number of cycles
Median (Range) of cycles administered459
12 (1-39)

Patients with cycles administered, n (%):
1 cycle2 cycles4 cycles5 cycles6 cycles8 cycles11 cycles
12 cycles
13 cycles
14 cycles
16 cycles

1 (3.2)2 (6.5)3 (9.7)2 (6.5)3 (9.7)3 (9.7)
1 (3.2)
1 (3.2)
1 (3.2)
1 (3.2)3 (9.7)

Patients with dose reductions, n (%)
Patients with 1 dose reduction, n (%)
Patients with 2 dose reductions, n (%)
Total number of dose reductions

13 (41.9)
10 (32.3)
3 (9.7)
34

Patients with dose increase, n (%)
Patients with 1 dose increase, n (%)
Patients with 2 dose increase, n (%)
Total number of dose increase

5 (16.1)
2 (6.5)3 (9.7)
24

Patients with dose interruptions, n (%)
Total number of dose interruptions

24 (77.4)
134

Reason for dose interruptions, n (%)
Adverse Event(s)Not reported
Other

21 (67.7)
1 (3.2)
11 (35.5)

Source: Table 14.4.1.2.1
If there were no patients receiving a particular number of cycles, this is not displayed in the table.
Patient can contribute to more than one reason.
Patients are counted only once for each reason. Per protocol the patients were enrolled to receive drug
treatment at 37.5 mg once a day.
If a patient receives treatment dose greater than the last dose received, then it is considered as dose increase.
If a patient receives treatment dose less than the last dose received, then it is considered as dose reduction.
Abbreviation: N = number of patients with at least 1 dose of study drug; n = number of patients who met thecriteria.

For the China subgroup, cumulative dose and RDI are summarized in Table 11. Overall, themedian RDI was 91.9% and median average daily dose administered was 34.5 mg.

PFIZER CONFIDENTIAL
Page 39

Page 39

Supplemental Clinical Study Report
Protocol A6181202
Table 11. Overall Cumulative Dose and Relative Dose Intensity – Safety Analysis Set;
China Subgroup
Total
N = 31
Actual cumulative dose (mg)Median
Mean
SD
Range

10100.014583.913194.37
1087.5 - 47550.0

Relative dose intensity (%)
Median
Mean
SD
Range

91.9
87.3
14.74
56.6 - 100.0

Average daily dose as administered (mg)Median
Mean
SD
Range

34.5
32.7
5.53
21.2 - 37.5

Source: Table 14.4.1.3.1
Actual Cumulative Dose is actual total dose taken in the cycle.
Actual Dose Intensity is actual total dose taken in the cycle divided by actual number of days in the cycle
including delays.
Relative Dose Intensity is a percentage of Actual to Intended Dose Intensities.
Average Daily Dose is actual total dose taken divided by actual number of days in the study including delays.
Abbreviations: N = number of patients with at least 1 dose of study drug; SD = standard deviation.

For the global population, by patient listings are provided for study drug administration
schedule in Table 16.2.5.1, dose modification in Table 16.2.5.1.1, cumulative dose and RDI
in 16.2.5.1.2, and for medication error in Table 16.2.5.1.3.
Adverse Events
Brief Summary of Adverse Events
In the global population, 1377 treatment-emergent adverse events (TEAEs) were reported in
104 (98.1%) patients, of which 770 TEAEs were reported in 59 (96.7%) patients in thetreatment-naïve cohort and 607 TEAEs in 45 (100.0%) patients in later-line cohort(Table 12). A total of 29 (27.4%) patients experienced an SAE, with similar proportions in
the 2 cohorts. Grade 5 TEAEs were reported in 4 (3.8%) patients, with similar proportions in
the 2 cohorts. Of the Grade 5 events reported, none was related to the study treatment(Table 14.3.1.3.1) and all were reported as a TEAE of disease progression(Table 14.3.1.2.9.1). Grade 3 or 4 TEAEs were reported in a higher proportion of patients inthe treatment-naïve (73.8%) than the later-line (66.7%) cohort. TEAEs resulted in temporary
discontinuation of the study drug were reported in 68 (64.2%) patients, and permanent
discontinuation in 22 (20.8%) patients. The study drug was reduced due to a TEAE in
PFIZER CONFIDENTIAL
Page 40

Page 40

Supplemental Clinical Study Report
Protocol A6181202
25 (23.6%) patients, with a higher proportion of patients in the treatment-naïve
(19 [31.1%] patients) than the later-line (6 [13.3%] patients) cohort.
Table 12. All-Causality Treatment-Emergent Adverse Events – Safety Analysis Set;
Global Population

Number of AEs
Patients, n (%)
Patients with AEs
Patients with SAEs
Patients with Grade 3 or 4 AEs
Patients with Grade 5 AEs
Patients permanently discontinued due to
AEs
Patients with dose reduced due to AEs
Patients with temporary discontinuation due
to AEsTreatment-Naïve
CohortN = 61

Later-Line Cohort
N = 45Total
N = 106

770

607

1377

59 (96.7)
17 (27.9)
45 (73.8)
2 (3.3)
11 (18.0)

45 (100.0)
12 (26.7)
30 (66.7)
2 (4.4)11 (24.4)

104 (98.1)
29 (27.4)
75 (70.8)
4 (3.8)22 (20.8)

19 (31.1)
41 (67.2)

6 (13.3)
27 (60.0)25 (23.6)
68 (64.2)

Source: Table 14.3.1.2.1
TEAEs were all AEs (serious and non-serious) that occurred for the first time on or after the first day of study
drug and include data up to 9999 days after last dose of study drug. Events that are continuations of baseline
abnormalities are considered TEAEs only if there is an increase in grade over baseline.
Except for the number of AEs patients are counted only once per cohort in each row.
SAEs - according to the investigator’s assessment.
MedDRA (version 21) coding dictionary applied.
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; N = number ofpatients with at least 1 dose of study drug; n = number of patients who met the criteria; SAE = serious adverse
event; TEAE = treatment-emergent adverse events.

In the China subgroup, all patients experienced at least 1 TEAE regardless of the causality(Table 13). A total of 414 TEAEs were reported in 31 patients. Overall, 8 (25.8%) patients
experienced an SAE. No Grade 5 TEAEs were reported. Overall, Grades 3 or 4 TEAEs
were reported in 25 (80.6%) patients compared with 70.8% in the global population(Table 12). Permanent or temporary discontinuations due to TEAEs or dose modifications
due to TEAEs were reported in a similar proportion of patients as in the global population.
In general, the proportions of patients experiencing TEAEs from the categories analyzed
were similar to those in the global population.

PFIZER CONFIDENTIAL
Page 41

Page 41

Supplemental Clinical Study Report
Protocol A6181202
Table 13. All-Causality Treatment-Emergent Adverse Events – Safety Analysis Set;
China Subgroup
Total
N = 31
Number of AEs

414

Patients, n (%):
Patients with AEs
Patients with SAEs
Patients with Grade 3 or 4 AEs
Patients with Grade 5 AEs
Patients permanently discontinued due to AEs
Patients with dose reduced due to AEs
Patients with temporary discontinuation due to AEs

31 (100.0)
8 (25.8)
25 (80.6)
05 (16.1)
6 (19.4)
18 (58.1)

Source: Table 14.3.1.2.1.1
TEAEs were all AEs (serious and non-serious) that occurred for the first time on or after the first day of study
drug and include data up to 9999 days after last dose of study drug. Events that are continuations of baseline
abnormalities are considered TEAEs only if there is an increase in grade over baseline.
Except for the number of AEs patients are counted only once per cohort in each row.
SAEs - according to the investigator’s assessment.
MedDRA (version 21.0) coding dictionary applied.
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; N = number ofpatients with at least 1 dose of study drug; n = number of patients who met the criteria; SAE = serious adverse
event; TEAE = treatment-emergent adverse events.

Incidence of Adverse Events
All-Causality Treatment-Emergent Adverse Events
In the global population, the most common TEAEs reported in ≥5% of patients in either
cohort regardless of causality are summarized by System Organ Class (SOC) and Preferred
Term (PT) in Table 14. Overall, the SOC with TEAEs reported at the highest by-patient
frequency was Gastrointestinal disorders reported in 94 (88.7%) patients, followed by Blood
and lymphatic system disorders in 70 (66.0%) patients and Skin and subcutaneous tissue
disorders in 67 (63.2%) patients. Similar to the results reported in the primary CSR,1 the
3 most commonly reported TEAEs were neutropenia reported in 60 (56.6%) patients,
followed by diarrhea in 55 (51.9%) patients, and leukopenia in 47 (44.3%) patients. These
3 TEAEs were reported in 60.7%, 54.1%, and 42.6% of patients in the treatment-naïve
cohort, respectively, compared to 51.1%, 48.9%, and 46.7% in the later-line cohort,respectively.

PFIZER CONFIDENTIAL
Page 42

Page 42Supplemental Clinical Study Report
Protocol A6181202
Table 14. All-Causality Treatment-Emergent Adverse Events Experienced by 5% ofPatients in Either Cohort by System Organ Class and Preferred Term (All
Cycles, All Grades) – Safety Analysis Set; Global Population
System Organ Class
Preferred Term

Treatment-Naïve
CohortN = 61n (%)

Later-Line Cohort
N = 45n (%)

Total
N = 106n (%)

59 (96.7)

45 (100.0)

104 (98.1)

38 (62.3)

32 (71.1)

70 (66.0)

11 (18.0)
26 (42.6)
4 (6.6)37 (60.7)
18 (29.5)

9 (20.0)
21 (46.7)
3 (6.7)23 (51.1)
15 (33.3)

20 (18.9)47 (44.3)
7 (6.6)60 (56.6)
33 (31.1)

Endocrine Disorders
Hypothyroidism

5 (8.2)5 (8.2)4 (8.9)3 (6.7)9 (8.5)8 (7.5)Eye disorders
Lacrimation increased

8 (13.1)
3 (4.9)6 (13.3)
014 (13.2)
3 (2.8)Gastrointestinal disorders
Abdominal distension
Abdominal pain
Abdominal pain upper
Ascites
Constipation
Diarrhoea
Dyspepsia
Dysphagia
Flatulence
Gastrooesophageal reflux
diseaseGingival bleeding
Mouth ulceration
NauseaOral Pain
Regurgitation
Stomatitis
Vomiting

53 (86.9)
4 (6.6)16 (26.2)
6 (9.8)1 (1.6)3 (4.9)33 (54.1)
8 (13.1)
2 (3.3)3 (4.9)41 (91.1)
3 (6.7)
11 (24.4)
7 (15.6)
3 (6.7)7 (15.6)
22 (48.9)
14 (31.1)
3 (6.7)
1 (2.2)94 (88.7)
7 (6.6)27 (25.5)
13 (12.3)
4 (3.8)10 (9.4)
55 (51.9)
22 (20.8)
5 (4.7)4 (3.8)4 (6.6)4 (8.9)8 (7.5)3 (4.9)4 (6.6)14 (23.0)
1 (1.6)3 (4.9)15 (24.6)
8 (13.1)

0
5 (11.1)
14 (31.1)
3 (6.7)0
6 (13.3)
10 (22.2)

3 (2.8)9 (8.5)28 (26.4)
4 (3.8)3 (2.8)21 (19.8)
18 (17.0)

35 (57.4)

29 (64.4)

64 (60.4)

11 (18.0)
3 (4.9)20 (32.8)
6 (9.8)5 (8.2)5 (8.2)
1 (1.6)7 (15.6)
1 (2.2)13 (28.9)
5 (11.1)
2 (4.4)3 (6.7)3 (6.7)18 (17.0)
4 (3.8)33 (31.1)
11 (10.4)
7 (6.6)8 (7.5)4 (3.8)Any AE
Blood and Lymphatic System
DisordersAnaemia
Leukopenia
Lymphopenia
Neutropenia
Thrombocytopenia

General disorders andadministration site conditions
Asthenia
Face oedema
Fatigue
Mucosal inflammation
OedemaOedema peripheral
Pain

PFIZER CONFIDENTIAL
Page 43

Page 43

Supplemental Clinical Study Report
Protocol A6181202
Table 14. All-Causality Treatment-Emergent Adverse Events Experienced by 5% ofPatients in Either Cohort by System Organ Class and Preferred Term (All
Cycles, All Grades) – Safety Analysis Set; Global Population
System Organ Class
Preferred Term

Treatment-Naïve
CohortN = 61n (%)
6 (9.8)Later-Line Cohort
N = 45n (%)

Total
N = 106n (%)

8 (17.8)

14 (13.2)

Hepatobiliary Disorders
Hepatic function abnormal
Liver injury

13 (21.3)
3 (4.9)3 (4.9)5 (11.1)
00

18 (17.0)
3 (2.8)3 (2.8)Immune System Disorders
Hypersensitivity

3 (4.9)3 (4.9)1 (2.2)0

4 (3.8)3 (2.8)Infections and Infestations
Influenza
Nasopharyngitis
Upper respiratory tract infection
Urinary tract infection

25 (41.0)
1 (1.6)6 (9.8)3 (4.9)6 (9.8)23 (51.1)
3 (6.7)2 (4.4)2 (4.4)3 (6.7)48 (45.3)
4 (3.8)8 (7.5)5 (4.7)9 (8.5)Investigations
Alanine aminotransferase
increased
Aspartate aminotransferase
increased
Blood alkaline phosphataseincreased
Blood bilirubin increased
Blood creatinine increased
Blood potassium decreased
Blood thyroid stimulating
hormone increased
Blood urine present
Haemoglobin decreased
Neutrophil count decreased
Protein urine present
Red blood cell count decreased
Weight decreased
Weight increased
White blood cell countdecreased
White blood cells urine positive

32 (52.5)

22 (48.9)

54 (50.9)

3 (4.9)8 (17.8)

11 (10.4)

5 (8.2)7 (15.6)

12 (11.3)

2 (3.3)3 (6.7)5 (4.7)

1 (1.6)
1 (1.6)3 (4.9)3 (6.7)3 (6.7)0

4 (3.8)4 (3.8)3 (2.8)5 (8.2)2 (4.4)7 (6.6)3 (4.9)4 (6.6)5 (8.2)
1 (1.6)2 (3.3)
11 (18.0)
5 (8.2)0
2 (4.4)3 (6.7)3 (6.7)3 (6.7)7 (15.6)
2 (4.4)3 (2.8)6 (5.7)8 (7.5)4 (3.8)5 (4.7)18 (17.0)
7 (6.6)6 (9.8)1 (2.2)7 (6.6)3 (4.9)03 (2.8)22 (36.1)

21 (46.7)

43 (40.6)

7 (11.5)
3 (4.9)2 (3.3)3 (4.9)7 (11.5)5 (8.2)7 (15.6)
3 (6.7)6 (13.3)
4 (8.9)4 (8.9)3 (6.7)14 (13.2)
6 (5.7)8 (7.5)7 (6.6)
11 (10.4)
8 (7.5)Pyrexia

Metabolism and Nutrition
Disorders
Decreased appetite
Hyperglycaemia
Hypocalcaemia
Hypoglycaemia
Hypokalaemia
Hypomagnesaemia

PFIZER CONFIDENTIAL
Page 44

Page 44

Supplemental Clinical Study Report
Protocol A6181202
Table 14. All-Causality Treatment-Emergent Adverse Events Experienced by 5% ofPatients in Either Cohort by System Organ Class and Preferred Term (All
Cycles, All Grades) – Safety Analysis Set; Global Population
System Organ Class
Preferred Term

Treatment-Naïve
CohortN = 61n (%)
2 (3.3)Later-Line Cohort
N = 45n (%)

Total
N = 106n (%)

7 (15.6)

9 (8.5)20 (32.8)

21 (46.7)

41 (38.7)

4 (6.6)2 (3.3)4 (6.6)3 (4.9)7 (11.5)

4 (8.9)7 (15.6)
3 (6.7)7 (15.6)
2 (4.4)8 (7.5)9 (8.5)7 (6.6)10 (9.4)
9 (8.5)

Nervous System Disorders
Dizziness
Dysgeusia
HeadacheParaesthesia

32 (52.5)
3 (4.9)14 (23.0)
12 (19.7)
3 (4.9)22 (48.9)
7 (15.6)
11 (24.4)
9 (20.0)054 (50.9)
10 (9.4)
25 (23.6)
21 (19.8)
3 (2.8)

Psychiatric Disorders
Insomnia

3 (4.9)0

5 (11.1)
3 (6.7)8 (7.5)3 (2.8)

Renal and Urinary Disorders
Proteinuria

10 (16.4)
5 (8.2)11 (24.4)
7 (15.6)

21 (19.8)
12 (11.3)

20 (32.8)

17 (37.8)

37 (34.9)

2 (3.3)2 (3.3)7 (11.5)
4 (6.6)6 (13.3)
4 (8.9)5 (11.1)
5 (11.1)

8 (7.5)6 (5.7)12 (11.3)
9 (8.5)42 (68.9)25 (55.6)

67 (63.2)

7 (11.5)
4 (6.6)00
5 (8.2)3 (4.9)1 (2.2)2 (4.4)4 (8.9)6 (13.3)
1 (2.2)08 (7.5)6 (5.7)4 (3.8)6 (5.7)6 (5.7)3 (2.8)19 (31.1)

14 (31.1)

33 (31.1)

5 (8.2)
1 (1.6)
7 (11.5)
8 (13.1)

1 (2.2)3 (6.7)3 (6.7)
1 (2.2)6 (5.7)4 (3.8)10 (9.4)
9 (8.5)

19 (31.1)

15 (33.3)

34 (32.1)

Hypophosphataemia
Musculoskeletal and Connective
Tissue Disorders
Arthralgia
Back pain
Muscle spasms
Myalgia
Pain in extremity

Respiratory, Thoracic andMediastinal Disorders
Cough
Dyspnoea
Epistaxis
Oropharyngeal pain
Skin and Subcutaneous Tissue
Disorders
Alopecia
Dry skin
Erythema
Hair colour changes
Hyperkeratosis
Nail discolouration
Palmar-plantar
erythrodysaesthesia
subcutaneous tissue syndrome
Pigmentation disorder
Pruritus
Rash
Skin exfoliation
Vascular disorders

PFIZER CONFIDENTIAL
Page 45

Page 45

Supplemental Clinical Study Report
Protocol A6181202
Table 14. All-Causality Treatment-Emergent Adverse Events Experienced by 5% ofPatients in Either Cohort by System Organ Class and Preferred Term (All
Cycles, All Grades) – Safety Analysis Set; Global Population
System Organ Class
Preferred Term
Deep vein thrombosis
Hypertension

Treatment-Naïve
CohortN = 61n (%)
3 (4.9)16 (26.2)

Later-Line Cohort
N = 45n (%)

Total
N = 106n (%)

1 (2.2)13 (28.9)

4 (3.8)29 (27.4)

Source: Table 14.3.1.2.9.1
Patients are only counted once per cohort for each row.
TEAEs were all AEs (serious and non-serious) that occurred for the first time on or after the first day of study
drug and include data up to 9999 days after last dose of study drug. Events that are continuations of baseline
abnormalities are considered TEAEs only if there is an increase in grade over baseline.
MedDRA (version 21.0) coding dictionary applied.
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; N = number ofpatients with at least 1 dose of study drug; n = number of patients who met the criteria; TEAE =treatment-emergent adverse event.

In the China subgroup, TEAEs reported in ≥3 patients regardless of causality are summarized
by SOC and PT in Table 15. Overall, the SOC with TEAEs reported at the highest by-patient
frequency was Blood and lymphatic system disorders reported in 27 (87.1%) patients,
followed by Gastrointestinal disorders and Skin and subcutaneous tissue disorders, both in
25 (80.6%) patients. Similar to the results reported in the China subgroup primary CSR,2 the
3 most commonly reported TEAEs were leukopenia reported in 24 (77.4%) patients,
followed by neutropenia in 23 (74.2%) patients, and thrombocytopenia in
15 (48.4%) patients, all in the SOC Blood and lymphatic disorders. Diarrhea, which was oneof the most commonly reported TEAEs in the global cohort (Table 14), was reported in ahigh proportion of patients in the China subgroup as well (14 [45.2%] patients).
In general, the type and frequency of the TEAEs reported in the global population and China
subpopulation were similar to those reported in the respective primary CSRs.1,2

PFIZER CONFIDENTIAL
Page 46

Page 46

Supplemental Clinical Study Report
Protocol A6181202
Table 15. All-Causality Treatment-Emergent Adverse Events Experienced by
3 Patients by System Organ Class and Preferred Term (All Cycles, All
Grades) – Safety Analysis Set; China Subgroup
System Organ Class
Preferred Term

Total
N = 31n (%)

Any AE

31 (100%)

Blood and Lymphatic System Disorders
Anaemia
Leukopenia
Neutropenia
Thrombocytopenia

27 (87.1)
7 (22.6)
24 (77.4)
23 (74.2)
15 (48.4)

Endocrine disorders
Hypothyroidism

4 (12.9)3 (9.7)

Eye disorders
Eyelid oedema

5 (16.1)
3 (9.7)

Gastrointestinal Disorders
Abdominal distension
Abdominal pain
Abdominal pain upper
Diarrhoea
Gastrooesophageal reflux disease
Mouth ulceration
NauseaRegurgitation
Stomatitis

25 (80.6)
4 (12.9)
8 (25.8)
6 (19.4)
14 (45.2)
3 (9.7)7 (22.6)
3 (9.7)3 (9.7)5 (16.1)

General Disorders and Administration Site Conditions
Fatigue
OedemaPyrexia

13 (41.9)
7 (22.6)
4 (12.9)
4 (12.9)

Hepatobiliary disorders
Hepatic function abnormal
Liver injury

6 (19.4)
3 (9.7)3 (9.7)

Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood bilirubin increased
Blood potassium decreased
Blood thyroid stimulating hormone increased
Blood urine presentElectrocardiogram T wave abnormal
Haemoglobin decreased
Neutrophil count decreased
Red blood cell count decreased
Weight decreased
PFIZER CONFIDENTIAL
Page 47

20 (64.5)5 (16.1)
6 (19.4)
3 (9.7)3 (9.7)5 (16.1)
3 (9.7)3 (9.7)3 (9.7)5 (16.1)
5 (16.1)
7 (22.6)

Page 47

Supplemental Clinical Study Report
Protocol A6181202
Table 15. All-Causality Treatment-Emergent Adverse Events Experienced by
3 Patients by System Organ Class and Preferred Term (All Cycles, All
Grades) – Safety Analysis Set; China Subgroup
System Organ Class
Preferred Term
Weight increased
White blood cell count decreased
White blood cells urine positive

Total
N = 31n (%)
4 (12.9)
4 (12.9)3 (9.7)

Metabolism and nutrition disorders
Decreased appetite
Hypocalcaemia
Hypokalaemia
Hypophosphataemia

11 (35.5)
4 (12.9)
6 (19.4)
5 (16.1)
3 (9.7)

Musculoskeletal Connective Tissue Disorders
Pain in extremity

11 (35.5)
4 (12.9)

Nervous system disorders
Dysgeusia
Headache
Hypogeusia

12 (38.7)
6 (19.4)
3 (9.7)3 (9.7)

Renal and Urinary Disorders
Proteinuria

9 (29.0)
9 (29.0)

Respiratory, Thoracic and Mediastinal Disorders
Oropharyngeal pain

7 (22.6)
3 (9.7)

Skin and Subcutaneous Tissue
Disorders
Alopecia
Hyperkeratosis
Nail discolouration
Palmar-plantar erythrodysaesthesia syndrome
Pigmentation disorder
Rash
Skin exfoliation

25 (80.6)
3 (9.7)5 (16.1)
3 (9.7)6 (19.4)
5 (16.1)
5 (16.1)
8 (25.8)

Vascular disorders
Hypertension

6 (19.4)
5 (16.1)

Source: Table 14.3.1.2.9.1.1
TEAEs were all AEs (serious and non-serious) that occurred for the first time on or after the first day of study
drug and include data up to 9999 days after last dose of study drug. Events that are continuations of baseline
abnormalities are considered TEAEs only if there is an increase in grade over baseline.
MedDRA (version 21.0) coding dictionary applied.
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; N = number ofpatients with at least 1 dose of study drug; TEAE = treatment-emergent adverse event.

PFIZER CONFIDENTIAL
Page 48

Page 48

Supplemental Clinical Study Report
Protocol A6181202
Treatment-Related Treatment-Emergent Adverse Events
For the global population, a summary of treatment-related TEAEs is presented in Table 16.
Of the total 1377 TEAEs reported (Table 12), 981 TEAEs were considered treatment-related.
At least 1 treatment-related TEAE was reported in a total of 101 (95.3%) patients;
57 (93.4%) patients in the treatment-naïve cohort and 44 (97.8%) patients in the later-line
cohort. Overall, 12 (11.3%) patients experienced a treatment-related SAE, with a higher
proportion of patients in the treatment-naïve (14.8% patients) than the later-line cohort(6.7% patients). There were no Grade 5 treatment-related TEAEs reported. Grade 3 or 4
treatment-related TEAEs were reported in a higher proportion of patients in thetreatment-naïve (37 [60.7%] patients) than the later-line (21 [46.7%] patients) cohort. A
treatment-related TEAE resulted in the study drug being either permanently or temporarily
discontinued in a total of 12.3% and 59.4% of the patients, respectively, with similar
proportions of patients in the 2 cohorts for both categories. The study drug was reduced due
to a treatment-related TEAE in a higher proportion of patients in the treatment-naïve
(31.1% patients) than the later-line (13.3% patients) cohort.
Table 16. Treatment-Related Treatment-Emergent Adverse Events – Safety Analysis
Set; Global Population
Treatment-Naïve Later-Line
CohortCohortN = 61
N = 45
Number of AEs
Patients, n (%)
Patients with AEs
Patients with SAEs
Patients with Grade 3 or 4 AEs
Patients with Grade 5 AEs
Patients permanently discontinued due to AEs
Patients with dose reduced due to AEs
Patients with temporary discontinuation due to AEs

Total
N = 106

577

404

981

57 (93.4)
9 (14.8)
37 (60.7)
08 (13.1)
19 (31.1)
37 (60.7)

44 (97.8)
3 (6.7)21 (46.7)
0
5 (11.1)
6 (13.3)
26 (57.8)

101 (95.3)
12 (11.3)
58 (54.7)
0
13 (12.3)
25 (23.6)
63 (59.4)

Source: Table 14.3.1.3.1
TEAEs were all AEs (serious and non-serious) that occurred for the first time on or after the first day of study
drug and include data up to 9999 days after last dose of study drug. Events that are continuations of baseline
abnormalities are considered TEAEs only if there is an increase in grade over baseline.
Patients are counted only once per cohort in each row.
SAEs - according to the investigator’s assessment.
MedDRA (version 21) coding dictionary applied.
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; N = number ofpatients with at least 1 dose of study drug; n = number of patients who met the criteria; SAE = serious adverse
event; TEAE = treatment-emergent adverse event.

In the China subgroup, treatment-related TEAEs are summarized in Table 17. Of the total
414 TEAEs reported (Table 13), 344 TEAEs were considered treatment-related. There wereno Grade 5 treatment-related TEAEs reported. Grade 3 or 4 treatment-related TEAEs werereported in 19 (61.3%) patients. A total of 5 (16.1%) patients experienced an SAE. A
PFIZER CONFIDENTIAL
Page 49

Page 49

Supplemental Clinical Study Report
Protocol A6181202
treatment-related TEAE resulted in the study drug being temporarily discontinued in
17 (54.8%) patients, reduced in 6 (19.4%) patients, and permanently discontinued in
3 (9.7%) patients.
Table 17. Treatment-Related Treatment-Emergent Adverse Events – Safety Analysis
Set; China Subgroup
Total
N = 31
Number of AEs

344

Patients, n (%)
Patients with AEs
Patients with SAEs
Patients with Grade 3 or 4 AEs
Patients with Grade 5 AEs
Patients permanently discontinued due to AEs
Patients with dose reduced due to AEs
Patients with temporary discontinuation due to AEs

31 (100.0)
5 (16.1)
19 (61.3)
03 (9.7)6 (19.4)
17 (54.8)

Source: Table 14.3.1.3.1.1
TEAEs were all AEs (serious and non-serious) that occurred for the first time on or after the first day of study
drug and include data up to 9999 days after last dose of study drug. Events that are continuations of baseline
abnormalities are considered TEAEs only if there is an increase in grade over baseline.
Patients are counted only once per cohort in each row.
SAEs - according to the investigator’s assessment.
MedDRA (version 21.0) coding dictionary applied.
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; N = number ofpatients with at least 1 dose of study drug; n = number of patients who met the criteria; SAE = serious adverse
event; TEAE = treatment-emergent adverse event.

For the global population, treatment-related TEAEs by SOC and PT reported at a frequencyof ≥5% in either cohort are presented in Table 18. Overall, the SOC with treatment-related
TEAEs reported at the highest by patient frequency was Gastrointestinal disorders reported in
83 (78.3%) patients, followed by Blood and lymphatic system disorders in 68 (64.2%)
patients, and Skin and subcutaneous tissue disorders in 64 (60.4%) patients. As reported in
the primary CSR,1 the 3 most commonly reported treatment-related TEAEs overall were
neutropenia reported in 58 (54.7%) patients, followed by diarrhea in 50 (47.2%) patients, andleukopenia in 47 (44.3%) patients. Neutropenia and diarrhea were reported in a higher
proportion of patients in the treatment-naïve cohort (59.0% and 49.2%, respectively) than in
the later-line cohort (48.9% and 44.4%, respectively); and leukopenia in 42.6% and46.7% patients in the 2 cohorts, respectively.
In general, the frequency pattern of the treatment-related TEAEs was similar to that
described for all-causality TEAEs (Table 14).

PFIZER CONFIDENTIAL
Page 50

Page 50

Supplemental Clinical Study Report
Protocol A6181202
Table 18. Treatment-Related Treatment-Emergent Adverse Events Experienced by≥5% of Patients in Either Cohort by System Organ Class and Preferred
Term (All Cycles, All Grades) – Safety Analysis Set; Global Population
Treatment-Naïve
CohortN = 61n (%)

Later-Line Cohort
N = 45n (%)

Total
N = 106n (%)

Any AE57 (93.4)

44 (97.8)

101 (95.3)

Blood and Lymphatic System Disorders
Anaemia
Leukopenia
Lymphopenia
Neutropenia
Thrombocytopenia

37 (60.7)
8 (13.1)
26 (42.6)
4 (6.6)36 (59.0)
18 (29.5)

31 (68.9)9 (20.0)
21 (46.7)
3 (6.7)22 (48.9)
15 (33.3)

68 (64.2)
17 (16.0)
47 (44.3)
7 (6.6)58 (54.7)
33 (31.1)

Endocrine Disorders
Hypothyroidism

5 (8.2)5 (8.2)4 (8.9)3 (6.7)9 (8.5)8 (7.5)Eye disorders
Lacrimation increased

7 (11.5)
3 (4.9)2 (4.4)0

9 (8.5)3 (2.8)Gastrointestinal disorders
Abdominal distension
Abdominal pain
Abdominal pain upper
Constipation
Diarrhoea
Dyspepsia
Flatulence
Gastrooesophageal reflux disease
Mouth ulceration
NauseaOral Pain
Regurgitation
Stomatitis
Vomiting

48 (78.7)
3 (4.9)7 (11.5)
3 (4.9)030 (49.2)
6 (9.8)3 (4.9)4 (6.6)4 (6.6)
11 (18.0)
1 (1.6)3 (4.9)14 (23.0)
5 (8.2)35 (77.8)
3 (6.7)2 (4.4)5 (11.1)
4 (8.9)20 (44.4)
11 (24.4)
0
4 (8.9)5 (11.1)
13 (28.9)
3 (6.7)0
6 (13.3)
4 (8.9)83 (78.3)
6 (5.7)9 (8.5)8 (7.5)4 (3.8)50 (47.2)
17 (16.0)
3 (2.8)8 (7.5)9 (8.5)24 (22.6)
4 (3.8)3 (2.8)20 (18.9)9 (8.5)29 (47.5)

19 (42.2)

48 (45.3)

7 (11.5)
18 (29.5)5 (8.2)5 (8.2)5 (8.2)2 (3.3)5 (11.1)
9 (20.0)
4 (8.9)2 (4.4)0
3 (6.7)12 (11.3)
27 (25.5)
9 (8.5)7 (6.6)5 (4.7)5 (4.7)10 (16.4)
3 (4.9)3 (4.9)1 (2.2)00

11 (10.4)
3 (2.8)3 (2.8)System Organ Class
Preferred Term

General disorders and administration site
conditions
Asthenia
Fatigue
Mucosal inflammation
OedemaOedema peripheral
Pyrexia
Hepatobiliary Disorders
Hepatic function abnormal
Liver injury

PFIZER CONFIDENTIAL
Page 51

Page 51

Supplemental Clinical Study Report
Protocol A6181202
Table 18. Treatment-Related Treatment-Emergent Adverse Events Experienced by≥5% of Patients in Either Cohort by System Organ Class and Preferred
Term (All Cycles, All Grades) – Safety Analysis Set; Global Population
Treatment-Naïve
CohortN = 61n (%)
14 (23.0)
3 (4.9)Later-Line Cohort
N = 45n (%)

Total
N = 106n (%)

9 (20.0)023 (21.7)
3 (2.8)Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood bilirubin increased
Blood potassium decreased
Blood thyroid stimulating hormone
increased
Blood urine present
Haemoglobin decreased
Neutrophil count decreased
Protein urine present
Red blood cell count decreased
Weight decreased
White blood cell count decreased

23 (37.7)
3 (4.9)5 (8.2)
1 (1.6)3 (4.9)15 (33.3)
5 (11.1)
5 (11.1)
3 (6.7)038 (35.8)8 (7.5)10 (9.4)
4 (3.8)3 (2.8)5 (8.2)2 (4.4)7 (6.6)3 (4.9)4 (6.6)5 (8.2)
1 (1.6)2 (3.3)3 (4.9)6 (9.8)02 (4.4)3 (6.7)3 (6.7)3 (6.7)3 (6.7)
1 (2.2)3 (2.8)6 (5.7)8 (7.5)4 (3.8)5 (4.7)6 (5.7)7 (6.6)

Metabolism and Nutrition Disorders
Decreased appetite
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hypophosphataemia

16 (26.2)
7 (11.5)5 (8.2)4 (6.6)
1 (1.6)

12 (26.7)
3 (6.7)6 (13.3)
1 (2.2)2 (4.4)5 (11.1)

28 (26.4)
10 (9.4)
8 (7.5)6 (5.7)6 (5.7)6 (5.7)11 (18.0)

13 (28.9)

24 (22.6)

3 (4.9)1 (1.6)3 (4.9)05 (8.2)2 (4.4)4 (8.9)2 (4.4)7 (15.6)
1 (2.2)5 (4.7)5 (4.7)5 (4.7)7 (6.6)6 (5.7)

Nervous System Disorders
Dizziness
Dysgeusia
HeadacheParaesthesia

24 (39.3)
2 (3.3)
13 (21.3)
7 (11.5)
3 (4.9)17 (37.8)
5 (11.1)
11 (24.4)
6 (13.3)
041 (38.7)
7 (6.6)24 (22.6)
13 (12.3)
3 (2.8)

Renal and Urinary Disorders
Proteinuria

6 (9.8)4 (6.6)7 (15.6)
5 (11.1)

13 (12.3)
9 (8.5)14 (23.0)

11 (24.4)

25 (23.6)

1 (1.6)3 (6.7)4 (3.8)System Organ Class
Preferred Term
Infections and Infestations
Nasopharyngitis

Musculoskeletal and Connective Tissue
Disorders
Arthralgia
Back Pain
Muscle spasms
Myalgia
Pain in extremity

Respiratory, Thoracic and Mediastinal
Disorders
Dyspnoea

PFIZER CONFIDENTIAL
Page 52

Page 52

Supplemental Clinical Study Report
Protocol A6181202
Table 18. Treatment-Related Treatment-Emergent Adverse Events Experienced by≥5% of Patients in Either Cohort by System Organ Class and Preferred
Term (All Cycles, All Grades) – Safety Analysis Set; Global Population
Treatment-Naïve
CohortN = 61n (%)
6 (9.8)Later-Line Cohort
N = 45n (%)

Total
N = 106n (%)

5 (11.1)

11 (10.4)

Skin and Subcutaneous Tissue Disorders
Alopecia
Dry skin
Erythema
Hair colour changes
Hyperkeratosis
Nail discolouration
Palmar-plantar erythrodysaesthesia
syndrome
Pigmentation disorder
Rash
Skin exfoliation

40 (65.6)
7 (11.5)
4 (6.6)00
5 (8.2)3 (4.9)24 (53.3)
1 (2.2)2 (4.4)3 (6.7)6 (13.3)
1 (2.2)064 (60.4)
8 (7.5)6 (5.7)3 (2.8)6 (5.7)6 (5.7)3 (2.8)19 (31.1)

14 (31.1)

33 (31.1)

5 (8.2)7 (11.5)
8 (13.1)

1 (2.2)3 (6.7)
1 (2.2)6 (5.7)
10 (9.4)
9 (8.5)

Vascular disorders
Hypertension

16 (26.2)
14 (23.0)

10 (22.2)
9 (20.0)26 (24.5)
23 (21.7)

System Organ Class
Preferred Term
Epistaxis

Source: Table 14.3.1.3.9.1
Patients are only counted once per cohort for each row.
TEAEs were all AEs (serious and non-serious) that occurred for the first time on or after the first day of study
drug and include data up to 9999 days after last dose of study drug. Events that are continuations of baseline
abnormalities are considered TEAEs only if there is an increase in grade over baseline.
MedDRA (version 21.0) coding dictionary applied.
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; N = number ofpatients with at least 1 dose of study drug; n = number of patients who met the criteria;
TEAE = treatment-emergent adverse event.

For the China subgroup, treatment-related TEAEs experienced by at least 3 patients overall
are presented by SOC and PT in Table 19. Overall, the SOC with treatment-related TEAEs
reported at the highest by patient frequency was Blood and lymphatic system disorders
reported in 27 (87.1%) patients, followed by Skin and subcutaneous tissue disorders reported
in 25 (80.6%) patients and Gastrointestinal disorders reported in 22 (71.0%) patients. All thereported all-causality TEAEs in the SOC Blood and lymphatic system disorders (Table 15)
were considered treatment-related. Therefore, the 3 most commonly reported all-causality
TEAEs were also the 3 most commonly reported treatment-related TEAEs and were all in the
SOC Blood and lymphatic system disorders: leukopenia reported in 24 (77.4%) patients,
followed by neutropenia in 23 (74.2%) patients, and thrombocytopenia in
15 (48.4%) patients. Diarrhea, which was one of the most commonly reported
treatment-related TEAEs in the global cohort (Table 18) was reported in a high proportion ofpatients in the China subgroup as well (13 [41.9%] patients).
PFIZER CONFIDENTIAL
Page 53

Page 53

Supplemental Clinical Study Report
Protocol A6181202
In general, most of the frequently reported TEAEs were treatment-related and the overallfrequency pattern of TEAEs was similar to that reported in the primary CSRs.1,2

PFIZER CONFIDENTIAL
Page 54

Page 54

Supplemental Clinical Study Report
Protocol A6181202
Table 19. Treatment-Related Treatment-Emergent Adverse Events Experienced by
3 Patients, by System Organ Class and Preferred Term (All Cycles, All
Grades) – Safety Analysis Set; China Subgroup
System Organ Class
Preferred Term

Total
N = 31n (%)

Any AE

31 (100%)

Blood and Lymphatic System Disorders
Anaemia
Leukopenia
Neutropenia
Thrombocytopenia

27 (87.1)
4 (12.9)
24 (77.4)
23 (74.2)
15 (48.4)

Endocrine disorders
Hypothyroidism

4 (12.9)3 (9.7)

Eye disorders
Eyelid oedema

5 (16.1)
3 (9.7)

Gastrointestinal Disorders
Abdominal distension
Abdominal pain
Abdominal pain upper
Diarrhoea
Gastrooesophageal reflux disease
Mouth ulceration
Regurgitation
Stomatitis

22 (71.0)
4 (12.9)3 (9.7)
4 (12.9)
13 (41.9)
3 (9.7)7 (22.6)
3 (9.7)5 (16.1)

General Disorders and Administration
Site Conditions
Fatigue
Oedema10 (32.3)
7 (22.6)
4 (12.9)

Hepatobiliary disorders
Hepatic function abnormal
Liver injury

5 (16.1)
3 (9.7)3 (9.7)

Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood bilirubin increased
Blood potassium decreased
Blood thyroid stimulating hormone increased
Blood urine presentElectrocardiogram T wave abnormal
Haemoglobin decreased
Neutrophil count decreased
Red blood cell count decreased
Weight decreased
White blood cell count decreased
PFIZER CONFIDENTIAL
Page 55

18 (58.1)
4 (12.9)
5 (16.1)
3 (9.7)3 (9.7)5 (16.1)
3 (9.7)3 (9.7)3 (9.7)5 (16.1)
5 (16.1)
3 (9.7)
4 (12.9)

Page 55

Supplemental Clinical Study Report
Protocol A6181202
Table 19. Treatment-Related Treatment-Emergent Adverse Events Experienced by
3 Patients, by System Organ Class and Preferred Term (All Cycles, All
Grades) – Safety Analysis Set; China Subgroup
System Organ Class
Preferred Term

Total
N = 31n (%)

Metabolism and nutrition disorders
Hypocalcaemia
Hypokalaemia

9 (29.0)
6 (19.4)
3 (9.7)

Musculoskeletal Connective Tissue Disorders
Pain in extremity

8 (25.8)
3 (9.7)

Nervous system disorders
Dysgeusia
Hypogeusia

10 (32.3)
6 (19.4)
3 (9.7)

Renal and Urinary Disorders
Proteinuria

6 (19.4)
6 (19.4)

Skin and Subcutaneous Tissue
Disorders
Alopecia
Hyperkeratosis
Nail discolouration
Palmar-plantar erythrodysaesthesia syndrome
Pigmentation disorder
Rash
Skin exfoliation

25 (80.6)
3 (9.7)5 (16.1)
3 (9.7)6 (19.4)
5 (16.1)
5 (16.1)
8 (25.8)

Vascular disorders
Hypertension

5 (16.1)
4 (12.9)

Source: Table 14.3.1.3.9.1.1
TEAEs were all AEs (serious and non-serious) that occurred for the first time on or after the first day of study
drug and include data up to 9999 days after last dose of study drug. Events that are continuations of baseline
abnormalities are considered TEAEs only if there is an increase in grade over baseline.
MedDRA (version 21.0) coding dictionary applied.
Abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; N = number ofpatients with at least 1 dose of study drug; n = number of patients who met the criteria;
TEAE = treatment-emergent adverse event.

Listing of Adverse Events by Patient
See Section 16.2.7.

PFIZER CONFIDENTIAL
Page 56

Page 56

Supplemental Clinical Study Report
Protocol A6181202
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
DeathsFor the global population, deaths are summarized in Table 20, individual listings of deaths
are presented in Table 14.3.2.1 and notice of death listing is provided in Table 14.3.2.1.3. Of
the 48 deaths reported in the overall population (45.3% of patients), the majority occurred
during the follow-up period (44 [41.5%] patients): 18 (29.5%) patients in the treatment-naïve
cohort and 26 (57.8%) patients in the later-line cohort. There were no deaths due to study
treatment toxicity. All deaths that occurred during the treatment period (4 [3.8%] patients)
and the majority of deaths during the follow-up period (38 [35.8%] patients) were considered
to be related to the disease under study. In 4 (3.8%) patients, the reason for death wasreported as “Other”: pneumonia and multiple organ failure (both in 1 patient), liver failure,
respiratory failure, and disease progression (in 1 patient each; 3 patients) (Table 14.3.2.1.3).
In 2 patients (1.9%) the reason for death was unknown.
Table 20. Summary of Deaths – Safety Analysis Set; Global Population
Treatment-Naïve
CohortN = 61n (%)

Later-Line Cohort
N = 45n (%)

Total
N = 106n (%)

Deathsa

20 (32.8)

28 (62.2)

48 (45.3)

Patients who died while on-treatmentb
Disease under study
Study treatment toxicity
Unknown
Other
Patients who died during follow-upc
Disease under study
Study treatment toxicity
UnknownOther

2 (3.3)2 (3.3)000
18 (29.5)
14 (23.0)0
2 (3.3)2 (3.3)2 (4.4)2 (4.4)000
26 (57.8)
24 (53.3)
00
2 (4.4)4 (3.8)4 (3.8)000
44 (41.5)
38 (35.8)
02 (1.9)4 (3.8)Source: Table 14.3.2.1.2
aInvestigator was notified of death of 1 patient enrolled in China in the treatment-naïve cohort after the patient
discontinued from study.
b
On-treatment deaths are those that occurred after the first dose of study drug and within 28 days of last dose.
c
Follow-up deaths are those that occurred after 28 days of last dose.
Abbreviations: N = number of patients with at least 1 dose of study drug; n = number of patients who met thecriteria.

For the China subgroup, deaths are summarized in Table 21, individual listings of deaths arepresented in Table 14.3.2.1.1 and notice of death listing is provided in Table 14.3.2.1.3.1. A
total of 10 (32.3%) patients died in the China subgroup, all during the follow-up period, andin 6 (19.4%) patients, death was considered to be related to the disease under study. There
were no deaths due to study treatment toxicity. In 3 (9.7%) patients, the reason for death was
PFIZER CONFIDENTIAL
Page 57

Page 57

Supplemental Clinical Study Report
Protocol A6181202
reported as “Other”: liver failure, respiratory failure, and disease progression (in 1 patienteach) (Table 14.3.2.1.3.1). In 1 (3.2%) patient the reason for death was unknown.
Table 21. Summary of Deaths – Safety Analysis Set; China Subgroup
Total
N = 31n (%)
Deathsa

10 (32.3)

Patients who died while on-treatmentb
Patients who died during follow-upc
Disease under study
Study treatment toxicity
UnknownOther0
10 (32.3)
6 (19.4)
01 (3.2)3 (9.7)

Source: Table 14.3.2.1.2.1
aInvestigator was notified of death of 1 patient enrolled in China in the treatment-naïve cohort after the patient
discontinued from study.
b
On-treatment deaths are those that occurred after the first dose of study drug and within 28 days of last dose.
c
Follow-up deaths are those that occurred after 28 days of last dose.
Abbreviations: N = number of patients with at least 1 dose of study drug; n = number of patients who met thecriteria.

Council for International Organizations of Medical Sciences (CIOMS) reports for deaths thatwere reported are available in Section 14.3.3.
Other Serious Adverse Events
For the global population, SAEs were reported in a total of 29 (27.4%) patients, of which
17 (27.9%) patients were in the treatment-naïve cohort and 12 (26.7%) patients in thelater-line cohort (Table 12). SAEs for the global population are presented by SOC, PT,severity grade and cohort in Table 14.3.2.2.2. Of the total SAEs reported, the severity was
Grade 5 in 4 (3.8%) patients, Grade 4 in 9 (8.5%) patients, Grade 3 in 14 (13.2%) patients,
and Grade 2 in 2 (1.9%) patients. The SOC with by far the most commonly reported SAEs
was Gastrointestinal disorders (13 [12.3%] patients). The most commonly reported SAEs
were abdominal pain (Grades 2 or 3) and disease progression (all Grade 5), both reported in
4 (3.8%) patients each. SAEs are detailed by the actual treatment group in Table 14.3.2.2.
For the China subgroup, SAEs were reported in a total of 8 (25.8%) patients, (Table 13).
SAEs are detailed by the actual treatment group in Table 14.3.2.2.1.1. The data for the China
subgroup on SAEs by SOC, PT, severity grade and cohort are part of the data for the global
population presented in Table 14.3.2.2.2.

PFIZER CONFIDENTIAL
Page 58

Page 58

Supplemental Clinical Study Report
Protocol A6181202
Other Significant Adverse Events
Thyroid Dysfunction
For the global population, all-causality TEAEs related to thyroid dysfunction were reported
in a total of 10 (9.4%) patients: 6 (9.8%) patients in the treatment-naïve cohort and4 (8.9%) patients in the later-line cohort (Table 14.3.1.2.9.5). All these TEAEs were ofseverity Grades 1 or 2. Overall, hypothyroidism was the single most commonly reported
TEAE in this category, reported in 8 (7.5%) patients.
For the China subgroup, all-causality TEAEs related to thyroid dysfunction were reported ina total of 5 (16.1%) patients (Table 14.3.1.2.9.5.1). Similar to the global population, all such
events were severity Grades 1 or 2; and hypothyroidism was the single most commonly
reported TEAE in this category, reported in 3 (9.7%) patients.
All-causality TEAEs related to thyroid stimulating hormone (TSH) were reported in the
global population in a total of 8 (7.5%) patients, all with severity Grades 1 or 2
(Table 14.3.1.2.9.6); and in the China subgroup in a total of 5 (16.1%) patients, all withseverity Grade 1 (Table 14.3.1.2.9.6.1).
Proteinuria
All-causality TEAEs related to proteinuria were of severity Grades 1, 2 or 3, reported in the
global population in a total of 15 (14.2%) patients (Table 14.3.1.2.9.7); and in the China
subgroup in a total of 10 (32.3%) patients (Table 14.3.1.2.9.7.1).
Narratives of Deaths, Other Serious Adverse Events, and Other Significant Adverse
EventsDeath Narratives
CIOMS reports of patients who died during the treatment period or the 28-day post-treatment
period were provided in the primary CSRs for the global population and the China subgroup.
Deaths occurring in the survival follow-up period are not included in the safety narratives(Section 14.3.3.1), as per the Safety Narratives Plan.
Other Serious Adverse Event Narratives
CIOMS reports for patients who experienced any treatment-related SAEs or SAEs resulting
in permanent discontinuation are provided in Sections 14.3.3.2.1 and 14.3.3.2.2, respectively.
Other Adverse Events Narratives
A prose narrative for a patient who experienced a non-serious AE that resulted indiscontinuation is provided in Section 14.3.3.3.1.
Clinical Laboratory Evaluation
Abnormal values that the investigator determined to be clinically significant were reported as
AEs.

PFIZER CONFIDENTIAL
Page 59

Page 59

Supplemental Clinical Study Report
Protocol A6181202
Laboratory data are presented for the global population in Table 16.2.8.1.1 andTable 16.2.8.1.4, and by NCI-CTC grade in Table 16.2.8.1.1.1. Laboratory test
abnormalities are listed by patient in Table 16.2.8.1.2 and by test in Table 16.2.8.1.3.
Hematology and Chemistry test results of Grade ≥3 are listed in Table 16.2.8.1.5 andTable 16.2.8.1.6, respectively. China subgroup data were not separately analyzed for thesesafety measures. There were no notable clinical laboratory evaluations reported other thanthose described in the primary CSR.1
Vital Signs, Electrocardiogram, and Physical Findings
China subgroup data was part of the global subpopulation data and were not separately
analyzed for these safety measures.
Vital Signs
Vital signs data for the SAS are provided in Table 16.2.8.2.1, vital signs change frombaseline in Table 16.2.8.2.2, and vital signs in specific categories in Table 16.2.8.2.4. There
were no notable vital signs observations reported other than those described in the primary
CSR.1
Electrocardiogram Results
ECG data for the SAS are provided in Table 16.2.8.3.1, and ECG change from baseline data
in Table 16.2.8.3.2. Changes in QTcB and QTcF interval within normal range at baseline to≥30 msec post-baseline were observed in 18 and 15 patients, respectively. Overall, meanchanges from baseline in QTcB and QTcF interval during and at the end of treatment were
small. Clinically meaningful ECG abnormalities, all of severity Grade 1, were reported as
AEs in the SOC Investigations in 5 (4.7%) patients (Table 14.3.1.3.9.1).
Physical Findings
Physical examinations data for the SAS for changes from screening are provided inTable 16.2.8.4.2.
CONCLUSIONS
Efficacy
As reported in the primary CSR, Study A6181202 met its primary objective of confirming
sunitinib treatment effect on PFS per investigator assessment in patients with advanced
metastatic, well-differentiated, unresectable pNETs per RECIST 1.0, with a medianinvestigator-assessed PFS of 13.2 months (95% CI: 10.9, 16.7). As estimation of OS was
one of the planned secondary endpoints of the study, patients were followed-up to collectsurvival data. OS data for the global population and the China subgroup presented in thissCSR are summarized as follows.
Global population:
Of the 106 patients enrolled, 61 patients were in the treatment-naïve cohort and45 patients in the later-line cohort; all were treated with sunitinib;
PFIZER CONFIDENTIAL
Page 60

Page 60

Supplemental Clinical Study Report
Protocol A6181202


At the end of the study, after a 3-year follow-up, 20 (32.8%) patients in thetreatment-naïve cohort and 28 (62.2%) patients in the later-line cohort had died;Survival probability at Year 1 was 88.3% (95% CI: 80.3, 93.2) and at Year 2 was
75.0% (95% CI: 65.3, 82.4);

Overall, the median OS for the global population was estimated to be 54.1 months(95% CI: 37.9, not reached). The median OS could not be determined for thetreatment-naïve cohort as the data were still immature; and was 37.9 months (95% CI:
22.9, 56.1) for the later-line cohort;

The median OS in this study was higher than the median OS reported in the pivotal study
A6181111 (38.6 months; 95% CI: 25.6, 56.4) in the sunitinib group (both treatment-naïve
and later-line patients);

Like in the primary CSR, a combined analysis was done to compare treatment-naïve
sunitinib-treated patients pooled from studies A6181202 and A6181111 (sunitinib arm)with placebo-treated patients from A6181111 study (placebo arm). However, the median
OS could not be determined for either arm because a high proportion of the patients were
censored: 80 (78.4%) patients and 29 (82.9%) patients, in the sunitinib and placebo arms,
respectively;It should be noted that survival follow-up was shorter in Study A6181111 (data cutoff
date, 15 April 2009; range for survival follow-up: 0.03 to 20.63 months) compared with
Study A6181202 (data cutoff date, 26 July 2018; range of survival follow-up, 0.03 to
70.83 months) leading to an imbalance in the follow-up between sunitinib and placebo
arms;



The estimated HR was 0.303 (95% CI: 0.100, 0.921), indicating a 69.7% reduction in riskof death with sunitinib treatment compared with placebo; and the difference wasstatistically significant (p-value = 0.013).

China subgroup:

A total of 31 patients were enrolled in China and treated with sunitinib;A high proportion of the patients were censored (21 [67.7%] patients), and the median
OS could not be determined;

Survival probability at Year 1 was 84.1% (95% CI: 66.0, 93.1) and at Year 2 was
77.7% (95% CI: 58.7, 88.7).

SafetyGlobal population:
Altogether 98.1% of patients experienced at least 1 all-causality TEAE and 95.3% of thepatients experienced at least 1 treatment-related TEAE;PFIZER CONFIDENTIAL
Page 61

Page 61

Supplemental Clinical Study Report
Protocol A6181202
Of the total 1377 TEAEs reported, 981 TEAEs were considered treatment-related;

SAEs were reported in a total of 29 (27.4%) patients and were of Grades 2 to 5;Grade 5 TEAEs were reported in 4 (3.8%) patients: in 2 patients each in thetreatment-naïve (3.3%) and the later-line (4.4%) cohorts; and none of these wastreatment-related;All-causality TEAEs resulted in the study drug being temporarily discontinued in
68 (64.2%) patients, reduced in 25 (23.6%) patients, and permanently discontinued in
22 (20.8%) patients;

Treatment-related TEAEs resulted in the study drug being temporarily discontinued in
63 (59.4%) patients, reduced in 25 (23.6%) patients, and permanently discontinued in
13 (12.3%) patients;

The 3 most commonly reported all-causality TEAEs were neutropenia reported in
60 (56.6%) patients, diarrhea in 55 (51.9%) patients, and leukopenia in
47 (44.3%) patients. This order was the same for treatment-related TEAEs: neutropenia
in 58 (54.7%) patients, diarrhea in 50 (47.2%) patients, and leukopenia in
47 (44.3%) patients;



There were no deaths due to study treatment toxicity. The majority of deaths occurred
during the follow-up period and were due to the disease under study. Deaths that
occurred during the treatment period (4 [3.8%] patients) were due to disease under study.

China subgroup:All patients experienced at least 1 all-causality TEAE and 1 treatment-related TEAE;Of the total 414 TEAEs reported, 344 TEAEs were considered treatment-related;

SAEs were reported in a total of 8 (25.8%) patients;

No Grade 5 TEAEs were reported;All-causality TEAEs resulted in the study drug being temporarily discontinued in
18 (58.1%) patients, reduced in 6 (19.4%) patients, and permanently discontinued in
5 (16.1%) patients;

Treatment-related TEAEs resulted in the study drug being temporarily discontinued in
17 (54.8%) patients, reduced in 6 (19.4%) patients, and permanently discontinued in
3 (9.7%) patients;

The 3 most commonly reported TEAEs were all in the SOC Blood and lymphatic
disorders and were all considered treatment-related TEAEs: leukopenia reported in
PFIZER CONFIDENTIAL
Page 62

Page 62

Supplemental Clinical Study Report
Protocol A6181202
24 (77.4%) patients, neutropenia in 23 (74.2%) patients, and thrombocytopenia in
15 (48.4%) patients;All the reported deaths (10 [32.3%] patients) occurred during the follow-up period andthe majority were due to the disease under study (6 [19.4%] patients).

In general, the safety findings in the global population and the China subgroup were similar
to those reported in the respective primary CSRs.
In summary, in Study A6181202, at the data cutoff date (26 July 2018), the median OS forthe global population was estimated to be 54.1 months (95% CI: 37.9, not reached). The OSdata were still immature to draw conclusions for the treatment-naïve cohort of the global
population and China subgroup. Safety findings in the global population and the China
subgroup were consistent with the known safety profile of sunitinib, and there were no
unexpected findings.
In conclusion, the sunitinib treatment effect was confirmed in patients with advanced
metastatic, well-differentiated, unresectable pNETs with an acceptable safety profile. The
benefit-risk profile of sunitinib was confirmed to be favorable for this patient population.

PFIZER CONFIDENTIAL
Page 63

Page 63

Supplemental Clinical Study Report
Protocol A6181202
REFERENCES

1

CSR A6181202. A Single Arm Open-Label International Multi-Center Study of the
Efficacy and Safety of Sunitinib Malate (SU011248, Sutent®) In Patients with
Progressive Advanced Metastatic Well-Differentiated Unresectable Pancreatic
Neuroendocrine Tumors. 11 November 2016.

2

Subgroup CSR for Chinese Patients at Sites in China A6181202. A Single Arm
Open-Label International Multi-Center Study of the Efficacy and Safety of Sunitinib
Malate (SU011248, Sutent®) In Patients with Progressive Advanced Metastatic
Well-Differentiated Unresectable Pancreatic Neuroendocrine Tumors.
09 November 2016.

3Öberg K, Jelic S. Neuroendocrine gastroenteropancreatic tumors: ESMO Clinicalrecommendation for diagnosis, treatment and follow-up. Ann Oncol 2009;20 (Suppl
4):150-3.

4Öberg K. Advances in chemotherapy and biotherapy of endocrine tumors. Curr Opin
Oncol 1998;10(1):58-65.

5Terris B, Scoazec JY, Rubbia L, et al. Expression of vascular endothelial growth factor
in digestive neuroendocrine tumors. Histopathol 1998;32(2):133-8.

6

Bergers G, Javaherian K, Lo KM, et al. Effects of angiogenesis inhibitors on multistage
carcinogenesis in mice. Science 1999;284(5415):808-12.

7

CSR A6181111. A Phase III Randomized, Double Blind Study of Sunitinib(SU011248, Sutent®) Versus Placebo in Patients with Progressive Advanced/Metastatic
Well Differentiated Pancreatic Islet Cell Tumors. 28 October 2009.

8

Supplemental CSR 3 A6181111. A Phase III Randomized, Double-Blind Study ofSunitinib (SU011248, Sutent®) Versus Placebo in Patients with Progressive
Advanced/Metastatic Well-Differentiated Pancreatic Islet Cell Tumors.
28 August 2014.

9

Solcia E, Klöppel G, Sobin LH. World Health Organization International HistologicalClassification of Tumours: Histological Typing of Endocrine Tumours: 2nd ed.
Springer-Verlag Berlin Heidelberg, 2000.

PFIZER CONFIDENTIAL
Page 64

Page 64