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IARTCremona, 06-06-2018
Quale spazio per la terapia biologica ?
Nicola Fazio, M.D., Ph. D.
Unit of Gastrointestinal Medical Oncology and
Neuroendocrine Tumors
European Institute of Oncology
Milan, Italy
VEGFR
PI3K
Akt
mTORC-1
PDGFREndothelial cell
Pericytes
PLC
PKC
SSTRs
Jak/STAT
RAS
RAF
MEK
ERK
IGF1-R
NET tumor cells
EVEROLIMUS
SUNITINIB SSA
SSA
Everolimus /
Sunitinib
Chemotherapy
PRRT
Liver-directed
treatments
Primary tumor
removal
Therapies for patients with advanced NET
‘70 ’80 ’90 2011
STZ in
pNET
Octreotide
IFN in carcinoid
syndrome
Lanreotide
in carcinoid
syndrome
Sunitinib
Everolimus
in pNET
PRRT in
GEP NET
Pasireotide
Liver-directed:
TACE/TAE
TARF/TARE
Bevacizumab
TMZ
Therapies for patients with advanced NETs
FDA/EMA Approved
Not FDA/EMA approved
2015
Lanreotide in
GEP
Octreotide in
midgut
2016
Everolimus in
non functioning
Lung and GI
Telotristatin refractory carcinoid
syndrome diarrhea
2017
Oxaliplatin
STZ: streptozotocin; TMZ: Temozolomide; IFN: Interferon; GEP: Gastroenteropancreatic; TACE: Trans-Arterial-Chemoembolization; TAE: Trans-arterial-embolization; TARE: Trans-arterialradioembolization
Oncological scientific societes NEN scientific societes
Italian NEN guidelines
NET guidelinesfrom several different scientific societes
Advanced pancreatic NET
trialPresented/pub
lishedtherapy PFS exp. arm PFS PLB arm setting
CLARINETCaplin, NEJM
2014
LAN A vs.
PLBNot reached 12 mo Well-diff
RADIANT-3Yao, NEJM
2011EVE vs. PLB 11.4 mo 5.4 mo Well-diff
NCT00510068Raymond,
NEJM 2011SUN vs. PLB 11 .4 mo 5.5 mo Well-diff
Phase III trial-related evidence in pNET
Yao, NEJM 2011
Raymond, NEJM 2011
Everolimus 11.4 m
Placebo 5.4 m
Sunitinib 11.4 m
Placebo 5.5 m
340 pts planned
171 enrolled
Early stop due to
significant difference
in deaths, SAEs, and
PFS
2006 Phase I
2008 Phase II
2011 Phase III
Preclinical
In the RIP1-Tag2 transgenic mouse model of pancreatic islet cell carcinoma,
sunitinib:
– reduced tumor burden and increased survival
– reduced endothelial cell population (VEGFR inhibition)
– reduced pericyte coverage (PDGFR inhibition)
Phase I
A study of sunitinib in solid tumors included 4 patients with
non-pancreatic NET, inducing:
– 1 confirmed PR (rectal NET with bulky peritoneal metastases; he
received sunitinib 75 mg/day 4/2 weekly)
– 1 minor response/SD
Pietras K & Hanahan D. J Clin Oncol 2005;23:939–52;
Yao V, et al. EORTC-NCI-AACR, Prague, 2007, Abstract 78
Faivre S, et al. J Clin Oncol 2006;24:25–35;
Sunitinib in NET:
preclinical and phase I experience
105 pts
with NET
(small cell excluded)
65 pts
With pNET
40 pts
with NET
from other origin
46
Non functioning
19 functioning
prior SSA
50%
prior SSA
30% Kulke et al., JCO 2008
2003 → 2005
Phase II trial
50 mg/day 4/6 weeks
PR m TTP
Pancreatic 16.7 % 7.7 mo
Non
pancreatic2.4 % 10.2 mo
Kulke et al., JCO 2008
Phase II trial
Phase III, Randomized, Double-Blind Study of Sunitinib
vs. Placebo in Patients with Advanced, Progressive,
Well-Differentiated Pancreatic Endocrine Tumors
R
A
N
D.
Accrual goal = 340
pts
Sunitinib 37.5 mg/day orally,
continuous daily dosing
(CDD)*
Arm A
Placebo
Arm B
1:1
Primary endpoint: PFS
Secondary endpoints:
OS, ORR, TTR, duration of response,
safety, patient-reported outcomes
Open-label sunitinib
protocol (NCT00443534 or
NCT00428220)
Crossover
Progression of disease
Non functioning, well differentiated, advanced pancreatic NET
Lanreotide
1
Everolimus
or
Sunitinib
CLARINET trialRADIANT-3 trial
A6181111 trial
2
or
Octreotide
Metastatic panNET:
Everolimus→ Sunitinib or Sunitinib→ Everolimus?
Criterion
Regulatory features ✖
Evidence ✖
Biological
background
✖
Clinical wisdom ✔
Everolimus Investigation in NETs
RADIANT (RAD001 in Advanced Neuroendocrine
Tumors)
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
RADIANT-3
RADIANT-2
RADIANT-1
EVE+OCT RAMSETE LUNA
EVE+OCT 1ST Line
ITMO
RADIANT-4
Phase III
Phase II
No validate predictive biomarker for sunitinib and everolimus so far
Martins et al., Targeted Oncol 2017
REVIEW ARTICLE
Predictive Markers of Response to Everolimus and Sunitinibin Neuroendocrine Tumors
Diana Martins1&Francesca Spada1
&Ioana Lambrescu1&Manila Rubino1
&
Chiara Cella1&Bianca Gibelli 2 &Chiara Grana3
&Dario Ribero4&Emilio Bertani 4 &
DavideRavizza5&Guido Bonomo6
&Luigi Funicelli 7&Eleonora Pisa8
&Dario Zerini 9 &
Nicola Fazio1&IEO ENETS Center of Excellence for GEP NETs
# Springer International Publishing Switzerland 2017
Abstract Neuroendocrine tumors (NETs) represent a large
and heterogeneous group of malignancies with various bio-
logical and clinical characteristics, depending on the site of
origin and the grade of tumor proliferation. In NETs, as in
other cancer types, molecularly targeted therapies have radi-
cally changed the therapeutic landscape. Recently two
targeted agents, the mammalian target of rapamycin inhibitor
everolimus and the tyrosine kinase inhibitor sunitinib, have
both demonstrated significantly prolonged progression free
survival in patients with advanced pancreatic NETs. Despite
these important therapeutic developments, there are still sig-
nificant limitationsto theuseof theseagentsdueto thelack of
accuratebiomarkers for predicting tumor responseand effica-
cy of therapy. In this review, we provide an overview of the
current clinical data for theevaluation of predictive factorsof
response to/efficacy of everolimus and sunitinib in advanced
pancreatic NETs. Surrogate indicators discussed include cir-
culating and tissue markers, as well as non-invasive imaging
techniques.
Key Points
Everolimus and sunitinib are widely investigated
targeted cancer therapies, and they are both globally
approved by regulatory authorities for the treatment of
pancreatic NETs.
The establishment of predictive markers of response to
everolimus and sunitinib in NETs is of extreme importance
for their efficient use.
Most efforts to define predictive biomarkers have failed,
with the exception of chromogranin-A and neuron-specific
enolase for advanced pancreatic NETs treated with
everolimus.
1 Introduction
Neuroendocrine tumors (NETs) comprise a heterogeneous
group of malignanciesoriginating from the diffuseendocrine
system. Even though NETsareconsidered a raremalignancy,
representing about two new cases per 100.000 persons per
year, their incidenceand prevalenceseem to berising steadily
[1]. Someof thepossible reasons for the increasing incidence
* Nicola Fazio
1 Unit of Gastrointestinal Medical Oncology and Neuroendocrine
Tumors, European Instituteof Oncology, IEO, 20141 viaRipamonti,
435 Milan, Italy
2 Division of Otolaryngology-Head and Neck Surgery, European
Instituteof Oncology, IEO, Milan, Italy
3 Division of Nuclear Medicine, European Instituteof Oncology, IEO,
Milan, Italy
4 Division of Hepatobiliopancreatic Surgery, European Instituteof
Oncology, IEO, Milan, Italy
5 Division of Endoscopy, European Instituteof Oncology, IEO,
Milan, Italy
6 Division of Interventional Radiology, European Instituteof
Oncology, IEO, Milan, Italy
7 Division of Radiology, European Instituteof Oncology, IEO,
Milan, Italy
8 Division of Pathology, European Institute of Oncology, IEO,
Milan, Italy
9 Division of Radiotherapy, European Instituteof Oncology, IEO,
Milan, Italy
Targ Oncol
DOI 10.1007/s11523-017-0506-5
Dual modulation of Mcl-1 and mTOR by sunitinib determines the
response of cancer cells
Elgendy et al., JCI 2016
Comparison of patient samples prior and post sunitinib treatment
suggests that increasing Mcl-1 levels and mTORC1 activity
correlates with resistance to sunitinib in patients
Resistance
Suni,nib
Beyond c
e
ll type-
specific threshold
GSK3b
ERK
Mcl-1
mTOR
Sensi,vity
Suni,nib
(higher doses)
GSK3b
ERK
Mcl-1
mTOR
Combinatorial treatment
Rapalogs/ Starva4on
Mcl-1 inhibitors
Sensi4za4on
Suni4nib
GSK3b
ERK
Mcl-1
mTOR
Everolimus —> Sunitinib vs. Sunitinib —> Everolimus
in renal cancer
RECORD-3 trial
Everolimus —> Sunitinib was not non-inferior
to the opposite sequence
An Italian real world analysis of sunitinib in panNET
• 73 pts with advanced pNET
• 82% with prior Everolimus
PR 19 %
SD 53 %
PFS 11 mo
mOS 36 mo
• (71% >/= 3 lines)
Confirmed activity and toxicity profile
even beyond Everolimus and/or PRRT
Panzuto et al., Pancreatology Nov 2017
Presented at the 14th Annual European Neuroendocrine Tumor Society (ENETS) Conference, March 8–10, 2017, Barcelona, Spain
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: Focus on Response RateE Raymond1, MH Kulke2, S Qin3, X Yu4, M Schenker5, A Cubillo6, W Lou7, J Tomasek8, E Thiis-Evensen9, K Fernandez10, B Rosbrook11, N Fazio12
1Paris Saint-Joseph Hospital Group, Paris, France; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4Fudan University Shanghai Cancer Center, Shanghai, China; 5Centrul de
Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 6Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 7Zhongshan Hospital, Fudan University, Shanghai, China; 8Masarykuv
onkologicky ustav/Klinika komplexní onkologické péče, Brno, Czech Republic; 9Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 10Pfizer Inc, Cambridge, MA, USA; 11Pfizer Inc, San Diego, CA, USA; 12IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy
REFERENCES1. 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.
ACKNOWLEDGMENTSWe 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. Previously presented in part at the 2017 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI), January 19–21, 2017, San Francisco, CA
For information on this poster, contact Eric Raymond, [email protected]
Copyright © 2017
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.
METHODSStudy 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 radiologic
review and per Choi criteria, 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.
RESULTSPatients
• Of 123 patients screened, 106 (61 treatment-naïve and 45 previously
treated) were enrolled at 25 centers in 15 countries (Figure 1).
• 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).
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
• 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 (95% CI) PFS as assessed by investigators was 13.2 months
(10.9–16.7); median (95% CI) PFS was similar in treatment-naïve and
previously treated patients (13.2 months [7.4–16.8] and 13.0 months
[9.2–20.4], respectively).
• Median (95% CI) PFS per Choi criteria was 18.7 months (5.6–not estimable)
and 16.5 months (7.4–22.9) in treatment-naïve and previously treated
patients, respectively (Figure 2).
• Median (95% CI) PFS as assessed by independent radiological review
was 11.1 months (7.4–16.6), in treatment-naive patients 11.1 months
(5.5–16.7), and in previously treated patients 9.5 months (7.4–18.4).
– 7 patients were censored due to lack of adequate baseline assessments.
Table 1: Demographics and Patient Baseline Characteristics
CharacteristicsTreatment-Naïve
n=61Previously Treated
n=45Total
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)
Any prior systemic chemotherapy, n (%)
0 45 (100) 45 (42.5)
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.
ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs
Figure 2: Kaplan–Meier Estimates of PFS Based on the Independent Third-Party
Radiology According to Choi Criteria PFS in Treatment-Naïve and Previously Treated
Patients With pNETs
PFS D
istribution Function
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
29
25
22
17
11
11
6
8
4
5
1
4
0
2
0
0
0
0
30 35 40 45
Treatment-naïve 61 25 18.7 (5.6–NE)
Previously treated 45 24 16.5 (7.4–22.9)
n Events mPFS (95% CI), mo
CI=confidence interval; mPFS=median progression-free survival; PFS=progression-free survival; NE=not estimable;
pNET=pancreatic neuroendocrine tumor
• ORR (95% CI) was 24.5% (16.7–33.8) according to the investigator
assessment.
• The ORR (95% CI) per Choi criteria was higher than the ORR per RECIST:
52.5% (39.3–65.4) and 55.6% (40.0–70.4) in treatment-naïve and
previously treated patients, respectively (Table 2).
•
Table 2: Best Observed Response Based on Independent Third-Party Radiology
According to Choi Criteria in Treatment-Naïve and Previously Treated Patients
With pNETs
Treatment-Naïve
n=61Previously Treated
n=45
Best overall response, n (%)
Complete response 0 1 (2.2)
Partial response 32 (52.5) 24 (53.3)
Stable disease 12 (19.7) 17 (37.8)
Progressive disease 9 (14.8) 2 (4.4)
Indeterminate 8 (13.1) 1 (2.2)
ORR,* n (%) 32 (52.5) 25 (55.6)
95% CI 39.3–65.4 40.0–70.4* Complete response + partial response.
CI=confidence interval; ORR=objective response rate; pNET=pancreatic neuroendocrine tumor; RECIST=Response Evaluation Criteria in
Solid Tumors
Median (95% CI) TTP was 14.5 months (11.0–16.7); median (95% CI) TTP
in treatment-naïve and previously treated patients was similar
(14.8 [7.5–16.8] and 14.5 [9.2–20.4] months, respectively).
– According to the Choi criteria, the median (95% CI) TTP was 18.7 months
(5.6–not estimable) for treatment-naïve patients and 16.7 months
(7.4–30.9) for previously treated patients.
• OS data were not mature at the time of data cutoff date (March 19, 2016);
29 (27.4%) patients had died and median (95% CI) OS was 37.8 months
(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.
Table 3: Treatment-Emergent, All-Causality Adverse Events
Adverse Events,* n (%)
Treatment-Naïven=61
Previously Treatedn=45
TotalN=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 crit eria.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; MedDRA=Medical Dictionary for Regulatory Activities
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 confi rm 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 profi le of sunitinib.
n The study confi rmed sunitinib is an effi cacious and safe treatment option in progressive, locally advanced and/or metastatic, well-differentiated, unresectable pNETs.
The Effi cacy and Safety of Sunitinib in Patients With Advanced Well-Differentiated Pancreatic Neuroendocrine TumorsEric 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 1Paris Saint-Joseph Hospital Group, Paris, France; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 5Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 6Zhongshan Hospital, Fudan University, Shanghai, China; 7Masaryk Memorial Cancer
Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 8Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 9No.307 Hospital, Academy of Military Medical Sciences, Beijing, China; 10Semmelweis University, Faculty of Medicine, 2nd Department of Internal Medicine, Budapest, Hungary; 11Fundeni Clinical Institute, Department of Medical Oncology, Bucharest, Romania; 12Andrew Love Cancer Center, Geelong Hospital, Victoria, Australia; 13Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika, Praha, Czech Republic; 14Cliniques Universitaires Saint-Luc, King Albert II Institute Cancerology and Hematology, Brussels, Belgium; 15University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa; 16Columbia University Medical Center, Division of Hematology/Oncology,
New York, NY, USA; 17Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 18Pfi zer Inc, Cambridge, MA, USA; 19Pfi zer Inc, San Diego, CA, USA; 20IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy
380
REFERENCES1. 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: Pfi zer Inc; 2015.
ACKNOWLEDGMENTSWe 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. Sufl iarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfi zer. Medical writing
support was provided by Mariko Nagashima, PhD, and Anne Marie Reid, PhD, of Engage Scientifi c Solutions, and was funded by Pfi zer.
For information on this poster, contact Eric Raymond, [email protected]
Copyright © 2017
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 signifi cant 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% confi dence 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
confi rm the effi cacy and safety of sunitinib in advanced and/or metastatic,
well-differentiated, unresectable pNETs.
METHODSStudy 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 confi rmed, 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 (defi ned 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.
RESULTSPatients
• 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 Profi le
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.
Effi cacy
• 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-naïven=61
Previously Treatedn=45
TotalN=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)
Any prior systemic chemotherapy, n (%) 0 45 (100) 45 (42.5)
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.
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
PFS D
istrib
utio
n F
unctio
n
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=confi dence 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 Treatedn=45
TotalN=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=confi dence 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 (March 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-naïven=61
Previously Treatedn=45
TotalN=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 crit eria.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; MedDRA=Medical Dictionary for Regulatory Activities
TTP (mo) 14.8 14.5 TTP (mo) 18.7 16.7
RECIST-based Choi-based
Raymond et al., ENETS 2017, Poster session
Manuscript under review
Sunitinib in panNET: data about first-line and cytoreductive effect
SSA
1
Everolimus
or Sunitinib
2
PRRT
4
Chemotherapy
5
Sunitinib
or Everolimus
3
Clinical trials
TAE / TACE / TARE
Liver surgery
RT
Primary tumor
removal
Metastatic indolent SSTR-2 + pancreatic NET
Minimal consensus statement:
Everolimus or sunitinib are generally recommended after failure of SSA or
chemotherapy in pancreatic NET.
Everolimus and sunitinib ………….. can be considered a first line therapy,
especially if SSA is not an option, and if systemic chemotherapy is not clinically
required, not feasible or not tolerated.
Advanced panNETs
2016 ENETS guidelines
Pavel et al., Neuroendocrinology Jan 2016
1
Chemotherapy
Everolimus
or
Sunitinib PRRT
Sunitinib
or
Everolimus
2 4 53
Advanced well differentiated panNET
According to ENETS guidelines
SSA
Prior therapy EVE PBO
Surgery n.r. n.r.
Radiotherapy 23 % 20 %
Chemotherapy 50 % 50 %
SSA 49 % 50 %
Yao et al., NEJM 2011
Everolimus in panNETs:
Prior chemotherapy
Raymond et al., NEJM 2011
Concomitant SSA treatment, n (%) of patients
Started prior to study and continued
Started during study
17 (20.5)
15 (18.1)
2 (2.4)
18 (22.0)
12 (14.6)
6 (7.3)
Sunitinib in panNETs:
Prior chemotherapy
Advanced
pancreatic NET G3
Type A = well diff. + Ki-67 21-55 %
Type B = poorly diff. + Ki-67 21-55%
Type C = poorly diff. + Ki-67 > 55%
Milione et al., Neuroendocrinology Mar 2016
Overall survival of 136 patients with GEP
NEC according to subtype
Neuroendocrinology (DOI:10.1159/000445165) © 2016 S. Karger AG, Basel 20
Table 1. Clinico-pathological features of 136 patients with NEC ALL Type A Type B Type C
Total 136 24 30 82
Gender Men 81 15 15 51
Women 55 9 15 31 Tumor site
Esophagus 5 0 1 4 Stomach 28 5 6 17
Duodenum 5 0 3 2 Ileum cecum appendix 17 4 3 10
Colon rectum 46 4 8 34 Pancreas 33 11 9 13
Gallbladder 2 0 0 2 Mitotic count /10HPF
<20 44 17 24 3 20-29 18 7 3 8 30 74 0 3 71
CD117 Negative 63 7 12 44 Positive 20 1 4 15 Missing 53 16 14 23
MMRd Absent 61 5 11 45
Present 6 2 2 2 Missing 69 17 17 35
Angio-invasion Absent 39 12 13 14
Present 67 7 12 48 Missing 30 5 5 20
Lymphocytic Infiltration Absent 94 14 19 61
Present 29 7 3 19 Missing 13 3 8 2
Stage (ENETS) I-II 9 2 1 6 III 45 7 15 23 IV 82 15 14 53
MMRd: mismatch repair protein defect.
Do
wnlo
ad
ed b
y:
EN
ET
S
19
8.1
43
.45.3
3 -
3/6
/20
16 1
2:0
0:5
9 P
M
Milione et al., Neuroendocrinology Mar 2016
• panNEC = 24% of the total population
• 30% of pNEC were NET G3 (or type A)
• Pancreas as the most frequent primary site among NET G3
GEP NEC heterogeneity: possible clinical implications
WD = well differentiated; PD = poorly differentiated
mPFS = 6 mo
mOS = 28 mo
Everolimus in panNET G3
Panzuto et al., Pancreas 2017
15 pts with panNET (all well/moderately differentiated) and 20-55% Ki-67
All pre-treated, mostly with chemotherapy
Clinical and biomarker evaluations of sunitinib in patients (pts) with
advanced well-differentiated grade 3 (G3) and poorly differentiated
neuroendocrine neoplasms (PD-NEN).
Dreyer et al., POSTER ASCO GI 2016
7/26 pts (23%) had SD or PR
3 pts were NET G3
Sunitinib in NET/NEC G3
IEO patient with liver mets from
moderately differentiated pancreatic NET, Ki67 40%
Resistant to platinum-based chemotherapy
1 month of Sunitinib 37.5 mg/d
Pancreatic “NET G3”
GETNE-1206 (SEQTOR): Phase III Study in Patients With
Advanced pNET
Unpublished data. Clinicaltrials.gov ID, NCT02246127.
Primary end point: rate of second PFS at 84 weeks of treatment
Progression
Everolimus
STZ +
5-FU
Everolimus
STZ +
5-FU
Arm A:
Arm B:
Compare efficacy and safety of everolimus followed by chemotherapy with
STZ + 5-FU upon progression, or the reverse sequence (chemotherapy with
STZ + 5-FU followed by everolimus upon progression)
26
GETNE 1206 (SEQTOR) phase III trial in patients with advanced panNETs
enrolling
Therapies sequencing in non-functioningmetastatic midgut NET: evidence
1 2
1
PRRT
2
Everolimus
3
Clinical trials
TAE / TACE / TARE
Liver surgery
RT
Primary tumor
removal
Metastatic SSTR-2 positive midgut NET
SSA
Sequence of therapies in refractory carcinoid syndrome
SSA dose/schedule
adjustmentPRRT IFN
Locoregional
treatments
diarrhea
SSA dose/schedule
adjustmentPRRT IFN
Locoregional
treatments
diarrhea
EVE
New TKIs
Novel TKIs in GEP NETs
Phase III
Phase III
Phase III
CDK 4/6 inhibitors
Neuroendocrinology (DOI:10.1159/000463386) © 2017 S. Karger AG, Basel 22
Fig. 1. Proposed and simplified mode of action of the CDK4/6 inhibitor LEE011 on
the cell cycle. a Activated CyclinD-CDK4/6-Rb axis leads to G1/S cell cycle
progression via the phosphorylation of Rb and subsequent activation of the
transcription factor E2F. b Blocking the CyclinD-CDK4/6-Rb axis leads to G1 phase
cell cycle arrest through either the endogenous CDK4/6 inhibitor p16 or the small
molecule CDK4/6 inhibitor LEE011.
Dow
nloa
ded
by:
Ist.E
urop
eo d
i Onc
olog
ia
193.
204.
98.2
- 2
/24/
2017
8:4
3:52
AM
CDK 4/6 inhibition in NET:
preclinical studies with RIBOCICLIB and PALBOCICLIB
Prada et al, Neuroendocrinology 2016
Tang L. et al., Clin Cancer Res 2012
CDK4/6 controls cell cycle progression
from G1 to S phase by regulating the
activity of Rb
Immune checkpoint inhibitors
PDR001 in GEP and Lung NET/NEC
Phase II multi-cohort international study
PDR001 binds to PD-1 so
blocking both PD-L1 and PD-L2
▪ Well differentiated:
▪ GI cohort (n=30)
▪ Pancreatic cohort (n=30)
▪ Thoracic cohort (n=30)
▪ Poorly differentiated:
▪ GEP cohort (n=20)
A multicohort phase II study of durvalumab plus tremelimumab for the
treatment of patients (PTS) with advanced neuroendocrine neoplasms
(NENs) of gastroenteropancreatic (GEP) or lung origin
(the DUNE trial-GETNE1601-).
Durvalumab(anti-PD-L1)
Tremelimumab(anti-CTLA-4)
Single-arm Phase II
126 pts
▪ Well differentiated:
▪ GI cohort (n=30)
▪ Pancreatic cohort (n=30)
▪ Thoracic cohort (n=30)
▪ Poorly differentiated:
▪ GEP cohort (n=20)
European Institute of Oncology, IEO,
Milan, Italy
ENETS Center of Excellence for GEP
NETs
IEO NET MDT