Presented at the American Society for Clinical Oncology Gastroenterology in January 2017 in San Francisco by Eric Raymond Background: Sunitinib was approved by the FDA in 2011 for treatment of progressive, well-differentiated, advanced pancreatic neuroendocrine tumors (pNETs) based on a pivotal phase III study (NCT00428597) that showed a significant increase in progression-free survival (PFS) over placebo following early study termination. Subsequently, the FDA requested a post-approval study to support these findings. Methods: In this open-label, phase IV clinical trial (NCT01525550), patients with progressive, well-differentiated, unresectable advanced/metastatic pNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to the phase III study. Primary endpoint was investigator-assessed PFS per RECIST 1.0. This study is ongoing. Results: Sixty one treatment-naïve and 45 previously treated patients with progressive pNETs were treated with sunitinib: mean age, 54.6 years; males, 59.4%; white, 63.2%; ECOG PS 0, 65.1% or PS 1, 34.0%; and prior somatostatin analog, 48.1% (treatment-naïve, 39.3%; previously treated, 60.0%). At the data cutoff date, 82 (77%) patients discontinued treatment, mainly due to disease progression (46%). Median duration of treatment was ~11.9 months. Investigator-assessed median PFS (mPFS) was 13.2 months (95% CI, 10.9–16.7) in the overall population, with comparable mPFS in treatment-naïve and previously treated patients (13.2 vs 13.0 months). mPFS per independent radiologic review was 11.1 months (95% CI, 7.4–16.6). Objective response rate (ORR) per RECIST was 24.5%: 21.3% in treatment-naïve and 28.9% in previously treated patients. Median overall survival, although not yet mature, was 37.8 months. Treatment-emergent, all-causality adverse events (AEs) reported by ≥20% of all patients included neutropenia, diarrhea, leukopenia, fatigue, hand–foot syndrome, hypertension, abdominal pain, dysgeusia, and nausea. Most common grade 3/4 AEs were neutropenia (22%) and diarrhea (9%). Conclusions: The mPFS of 13.2 months and ORR of 24.5% observed in this study support the outcomes of the pivotal phase III study of sunitinib in pNETs and confirm its activity in this setting. AEs were consistent with known safety profile of sunitinib.

1. Presented at the 2017 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI), January 19–21, 2017, San Francisco, CA
CONCLUSIONS
n Median PFS of 13.2 months (95% CI, 10.9–16.7) and ORR of 24.5% (95% CI,
16.7–33.8) observed in this phase IV trial support the outcomes of the pivotal
phase III trial of sunitinib in pNETs and confirm its activity in this setting.
n OS data were not mature at the time of the primary analysis.
n AEs were consistent with the known safety profile of sunitinib.
n The study confirmed sunitinib is an efficacious and safe treatment option
in progressive, locally advanced and/or metastatic, well-differentiated,
unresectable pNETs.
The Efficacy and Safety of Sunitinib in Patients With Advanced Well-Differentiated Pancreatic Neuroendocrine Tumors
Eric Raymond1
, Matthew H Kulke2
, Shukui Qin3
, Michael Schenker4
, Antonio Cubillo5
, Wenhui Lou6
, Jiri Tomasek7
, Espen Thiis-Evensen8
, Jianming Xu9
, Karoly Racz10
, Adina E Croitoru11
, Mustafa Khasraw12
, Eva Sedlackova13
, Ivan Borbath14
, Paul Ruff15
,
Paul E Oberstein16
, Tetsuhide Ito17
, Kathrine C Fernandez18
, Brad Rosbrook19
, Nicola Fazio20
1
Paris Saint-Joseph Hospital Group, Paris, France; 2
Dana-Farber Cancer Institute, Boston, MA, USA; 3
PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4
Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 5
Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 6
Zhongshan Hospital, Fudan University, Shanghai, China; 7
Masaryk Memorial Cancer
Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 8
Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 9
No.307 Hospital, Academy of Military Medical Sciences, Beijing, China; 10
Semmelweis University, Faculty of Medicine, 2nd Department of Internal Medicine, Budapest, Hungary; 11
Fundeni Clinical Institute, Department of Medical Oncology, Bucharest, Romania;
12
Andrew Love Cancer Center, Geelong Hospital, Victoria, Australia; 13
Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika, Praha, Czech Republic; 14
Cliniques Universitaires Saint-Luc, King Albert II Institute Cancerology and Hematology, Brussels, Belgium; 15
University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa; 16
Columbia University Medical Center, Division of Hematology/Oncology,
New York, NY, USA; 17
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 18
Pfizer Inc, Cambridge, MA, USA; 19
Pfizer Inc, San Diego, CA, USA; 20
IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy
380
REFERENCES
1. American Cancer Society. Cancer Facts & Figures 2016. Atlanta, GA.
2. Raymond E, et al. N Engl J Med 2011;364:501-13.
3. Faivre S, et al. Ann Oncol 2016; Nov 10 [Epub ahead of print].
4. Sutent®
(sunitinib malate) prescribing information. New York, NY: Pfizer Inc; 2015.
ACKNOWLEDGMENTS
We thank the participating patients and their families, as well as the global network of research nurses, trial
coordinators, and operations staff for their contributions, and investigators who participated in this trial, including:
M. Michael (Australia); X. Yu, Y. Shen and L. Jia (China); P. Hammel (France); S. Skrikhande (India); C. Morizane
(Japan); J. Sufliarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfizer. Medical writing
support was provided by Mariko Nagashima, PhD, and Anne Marie Reid, PhD, of Engage Scientific Solutions, and
was funded by Pfizer.
For information on this poster, contact x xxxxx at xxxx.xxxx
Copyright © 2016
INTRODUCTION
• Pancreatic neuroendocrine tumors (pNETs) are rare tumors. Of an estimated
53,070 new cases of pancreatic cancers expected in the US in 2016, pNETs
account for fewer than 5%.1
• Due to their relatively indolent nature, the majority of patients are diagnosed
with metastatic pNETs, for whom treatment options
are limited.
• pNETs are highly vascularized tumors; aberrant expression of vascular
endothelial growth factor (VEGF) and its receptors, which play vital roles in tumor
angiogenesis, has been observed.
• Sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI) of angiogenesis,
showed a significant increase in progression-free survival (PFS) over placebo in
well-differentiated, advanced and/or metastatic pNETs in a pivotal phase III
clinical trial (ClinicalTrials.gov NCT00428597).2
• The trial was terminated early after more-serious adverse events (AEs) and deaths
were observed in the placebo arm and a difference in PFS favored the sunitinib arm
(hazard ratio [HR] 0.42; 95% confidence interval [CI], 0.26–0.66; P<0.001; median:
11.4 vs 5.5 months).
– The median (95% CI) 5-year overall survival (OS) was 38.6 (25.6–56.4) months for
sunitinib and 29.1 (16.4–36.8) months for placebo (HR 0.73; 95% CI, 0.50–1.06;
P=0.094), with 69% of placebo patients having crossed over to sunitinib.3
• In 2010 and 2011, sunitinib was approved by the European Medicines Agency
and US Food and Drug Administration (FDA), respectively, for the treatment of
patients with progressive, locally advanced and/or metastatic, well-differentiated,
unresectable pNETs.4
OBJECTIVES
• This phase IV clinical trial (ClinicalTrials.gov NCT01525550) was conducted
as post-approval commitments to the FDA and other regulatory agencies to
confirm the efficacy and safety of sunitinib in advanced and/or metastatic,
well-differentiated, unresectable pNETs.
METHODS
Study Design
• This multinational, single-arm, open-label, phase IV clinical trial is ongoing.
• The primary endpoint is investigator-assessed PFS per the Response Evaluation
Criteria in Solid Tumors (RECIST) v1.0.
• Secondary endpoints include PFS assessed by the independent radiological review,
time to tumor progression (TTP), objective response rate (ORR), OS, and safety.
Key Eligibility Criteria
• Histologically or cytologically confirmed, well-differentiated, unresectable or
metastatic pNETs with documented progression within 12 months of study
enrollment.
• Not amenable to surgery, radiation, or combined modality therapy with curative
intent.
• Presence of ≥1 measurable target lesion per RECIST v1.0.
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
• No pre-existing uncontrolled hypertension (ie, blood pressure >150/100 mmHg
despite medical therapy).
• No prior treatment with TKIs, anti-VEGF, or other angiogenesis inhibitors.
Treatment and Assessments
• Patients received 37.5 mg sunitinib orally once a day on a continuous daily-dosing
regimen.
– Sunitinib dose could be increased to 50 mg daily any time after 8 weeks of
treatment initiation in patients without treatment response who experienced
only grade 1 or lower nonhematologic or grade 2 or lower hematologic
treatment-related AEs.
– Dose could be temporarily interrupted or reduced to 25 mg daily to manage
severe toxicity.
• Somatostatin analogs for control of symptoms were permitted at the investigator’s
discretion.
• Radiologic tumor assessments were conducted at screening, Cycle 2 Day 1, Cycle 3
Day 1, and every 2 cycles thereafter; tumor responses were evaluated per RECIST
v1.0 criteria.
• Safety was monitored throughout the study and AEs were graded according to the
National Cancer Institute Common Terminology Criteria for Adverse Events v3.0.
Statistical Analyses
• More than 80 patients were to be enrolled: 40 treatment-naïve (defined as
those who never received systemic antitumor therapy; somatostatin analogs for
symptomatic control were allowed) and 40 previously treated patients.
• Median PFS and 95% CI were estimated using the Kaplan–Meier method for the
entire population as well as separately for treatment-naïve and previously treated
patients.
• Descriptive statistics were used to summarize other parameters.
RESULTS
Patients
• Of 123 patients screened, 106 (61 treatment-naïve and 45 previously treated) were
enrolled at 25 centers in 15 countries (Figure 1).
Figure 1: Trial Profile
123 patients screened
106 patients enrolled
61 txt-naïve patients treated 45 previously treated patients treated
39 previously treated patients discontinued txt
23 Objective progression/relapse
8 Adverse events
1 Refusal of txt for reason other than AE
2 Global health deterioration
1 Death
4 Other
43 txt-naïve patients discontinued txt
26 Objective progression/relapse
6 Adverse events
4 Refusal of txt for reason other than AE
2 Global health deterioration
1 Death
4 Other
Efficacy analysis: 61 txt-naïve patients
Safety analysis: 61 txt-naïve patients
45 previously treated patients
45 previously treated patients
AE=adverse event; Txt=treatment
• Patient demographics and baseline characteristics are summarized in Table 1.
• More than half (n=64/106, 60.4%) of patients had a nonfunctioning tumor and
17.9% had a functioning tumor (unknown for 21.7%
of patients).
• In regard to prior locoregional treatment, 18.9% of patients had trans-arterial
chemoembolization; radiofrequency ablation (3.8%); or trans-arterial embolization,
percutaneous injections, or microwave ablation (2.8% each).
• Median (range) treatment duration in the total population was 11.7 months
(0.2–40.3): 12.2 months (0.2–35.9) in treatment-naïve vs 10.2 months (0.5–40.3)
in previously treated patients.
Efficacy
• Median PFS as assessed by investigators was 13.2 months (95% CI, 10.9–16.7);
median PFS was similar in treatment-naïve and previously treated patients
(13.2 months [95% CI, 7.4–16.8] and 13.0 months [95% CI, 9.2–20.4],
respectively; Figure 2).
• Median PFS as assessed by independent radiological review was 11.1 months (95%
CI, 7.4–16.6), in treatment-naive patients 11.1 months (95% CI, 5.5–16.7), and in
previously treated patients 9.5 months (95% CI, 7.4–18.4).
– 7 patients were censored due to lack of adequate baseline assessments.
Table 1: Demographics and Patient Baseline Characteristics
Characteristics
Treatment-naïve
n=61
Previously
Treated
n=45
Total
N=106
Age, years, mean (SD) 55.4 (8.9) 53.5 (9.1) 54.6 (9.0)
Gender, n (%)
Male 30 (49.2) 33 (73.3) 63 (59.4)
Female 31 (50.8) 12 (26.7) 43 (40.6)
Race, n (%)
White 32 (52.5) 35 (77.8) 67 (63.2)
Black 2 (3.3) 0 2 (1.9)
Asian 27 (44.3) 10 (22.2) 37 (34.9)
ECOG PS, n (%)
0 39 (63.9) 29 (64.4) 68 (64.2)
1 22 (36.1) 16 (35.6) 38 (35.8)
No. of involved disease sites,* n (%)
1 24 (39.3) 9 (20.0) 33 (31.1)
2 19 (31.1) 22 (48.9) 41 (38.7)
3 11 (18.0) 8 (17.8) 19 (17.9)
4 3 (4.9) 3 (6.7) 6 (5.7)
>4 4 (6.6) 3 (6.7) 7 (6.6)
Tumor site,* n (%)
Liver 57 (93.4) 41 (91.1) 98 (92.5)
Pancreas 22 (36.1) 25 (55.6) 47 (44.3)
Lymph node, distant 16 (26.2) 13 (28.9) 29 (27.4)
Lymph node, regional 13 (21.3) 7 (15.6) 20 (18.9)
Lung 3 (4.9) 3 (6.7) 6 (5.7)
Other 10 (16.4) 10 (22.2) 20 (18.9)
Prior systemic chemotherapy, n (%)
Any 0 45 (100) 45 (42.5)
Neoadjuvant 0 2 (4.4) 2 (1.9)
Adjuvant 0 4 (8.9) 4 (3.8)
Advanced/metastatic 0 39 (86.7) 39 (36.8)
Prior SSA,†
n (%) 24 (39.3) 27 (60.0) 51 (48.1)
Ki-67 index, mean (SD) 6.7 (5.0) 8.4 (7.2) 7.4 (6.0)
* Included both target and nontarget sites; sites with multiple lesions were counted once.
† Patients with regimens that consist only of somatostatin analogs were considered treatment-naïve.
ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs
Figure 2: Kaplan–Meier Estimates of PFS in Treatment-Naïve and Previously Treated
Patients With pNETs, Assessed by Investigators
PFSDistributionFunction
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 5 10 15 20 25
Time (Months)
No. at risk:
Treatment-naïve
Previously treated
61
45
41
29
32
20
14
10
8
8
6
4
0
4
0
2
0
1
0
0
30 35 40 45
Treatment-naïve 61 37 13.2 (7.4–16.8)
Previously treated 45 28 13.0 (9.2–20.4)
n Events mPFS (95% CI), mo
CI=confidence interval; mPFS=median progression-free survival; PFS=progression-free survival; pNETs=pancreatic neuroendocrine tumors
• ORR was 24.5% (95% CI, 16.7–33.8) according to the investigator assessment
(Table 2).
•
Table 2: Best Observed Response by RECIST, Assessed by Investigators
Treatment-naïve
n=61
Previously
Treated
n=45
Total
N=106
Best overall response, n (%)
Complete response 2 (3.3) 1 (2.2) 3 (2.8)
Partial response 11 (18.0) 12 (26.7) 23 (21.7)
Stable disease 40 (65.6) 29 (64.4) 69 (65.1)
Progressive disease 7 (11.5) 2 (4.4) 9 (8.5)
Indeterminate 1 (1.6) 1 (2.2) 2 (1.9)
ORR,* n (%) 13 (21.3) 13 (28.9) 26 (24.5)
95% CI 11.9–33.7 16.4–44.3 16.7–33.8
* Complete response + partial response.
CI=confidence interval; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors
Median TTP was 14.5 months (95% CI, 11.0–16.7); median TTP in treatment-naïve
and previously treated patients was similar (14.8 [95% CI, 7.5–16.8] and 14.5
[95% CI, 9.2–20.4] months, respectively).
• OS data were not mature at the time of data cutoff date (Mar 19, 2016); 29 (27.4%)
patients had died and median OS was 37.8 months (95% CI, 33.0–not estimable).
Safety
• Most-common treatment-emergent, all-grade AEs experienced by all patients treated
with sunitinib included neutropenia, diarrhea, and leukopenia (Table 3).
– No major differences were observed in the incidence of AEs reported by treatment-
naïve vs previously treated patients, except dyspepsia, nausea, and neutropenia.
• Percentage of treatment-naïve and previously treated patients who experienced
Grade 3 or 4 AEs was comparable; serious AEs were also comparable: 24.6% (n=15) vs
24.4% (n=11), respectively.
• 15 (24.6%) treatment-naïve and 5 (11.1%) previously treated patients had sunitinib
dose reductions due to AEs; 8 (13.1%) and 10 (22.2%) patients, respectively,
discontinued treatment due to AEs.
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Table 3: Treatment-Emergent, All-Causality Adverse Events
Adverse Events,* n (%)
Treatment-naïve
n=61
Previously Treated
n=45
Total
N=106
All
Grades
Grade
3/4
All
Grades
Grade
3/4
All
Grades
Grade
3/4
Neutropenia 37 (60.7) 13 (21.3) 22 (48.9) 10 (22.2) 59 (55.7) 23 (21.7)
Diarrhea 32 (52.5) 7 (11.5) 22 (48.9) 3 (6.7) 54 (50.9) 10 (9.4)
Leukopenia 25 (41.0) 4 (6.6) 21 (46.7) 3 (6.7) 46 (43.4) 7 (6.6)
Fatigue 19 (31.1) 1 (1.6) 14 (31.1) 0 (0.0) 33 (31.1) 1 (0.9)
Hand–foot 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)
Hypertension 16 (26.2) 4 (6.6) 11 (24.4) 2 (4.4) 27 (25.5) 6 (5.7)
Abdominal pain 16 (26.2) 2 (3.3) 10 (22.2) 3 (6.7) 26 (24.5) 5 (4.7)
Dysgeusia 14 (23.0) 0 (0.0) 11 (24.4) 0 (0.0) 25 (23.6) 0 (0.0)
Nausea 11 (18.0) 0 (0.0) 14 (31.1) 1 (2.2) 25 (23.6) 1 (0.9)
Dyspepsia 7 (11.5) 0 (0.0) 14 (31.1) 0 (0.0) 21 (19.8) 0 (0.0)
Headache 12 (19.7) 0 (0.0) 9 (20.0) 0 (0.0) 21 (19.8) 0 (0.0)
Stomatitis 13 (21.3) 2 (3.3) 6 (13.3) 1 (2.2) 19 (17.9) 3 (2.8)
Vomiting 8 (13.1) 1 (1.6) 10 (22.2) 1 (2.2) 18 (17.0) 2 (1.9)
Asthenia 10 (16.4) 0 (0.0) 7 (15.6) 2 (4.4) 17 (16.0) 2 (1.9)
Abdominal pain upper 5 (8.2) 1 (1.6) 7 (15.6) 1 (2.2) 12 (11.3) 2 (1.9)
ALT increased 2 (3.3) 1 (1.6) 9 (20.0) 0 (0.0) 11 (10.4) 1 (0.9)
AST increased 4 (6.6) 1 (1.6) 7 (15.6) 1 (2.2) 11 (10.4) 2 (1.9)
Constipation 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)
Dizziness 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)
Hypophosphatemia 2 (3.3) 2 (3.3) 7 (15.6) 3 (6.7) 9 (8.5) 5 (4.7)
Myalgia 2 (3.3) 0 (0.0) 7 (15.6) 0 (0.0) 9 (8.5) 0 (0.0)
Adverse events are listed by highest to lowest % for Total/All Grades patients.
* Adverse events reported by ≥15% in any treatment group per MedDRA criteria.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; MedDRA=Medical Dictionary for Regulatory Activities