Neuroendocrine Tumors in 2016

NEUROENDOCRINE TUMORS:
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Asyut Clinical Oncology Annual Conference
NOVARTIS Symposium
23/02/2016
“Capture a MACRO Portrait”

Disclosures:
• Amgen
• Merck Serono
• Janssen Cilag
• Astra Zeneca
• Pfizer
• Astellas.
• Hoffman La Roche
• Novartis

Challenges:
• Rare
• One Cell of Origin  Many Locations  Many Faces.
• +/- Hormonal Syndromes.
• Problems of Diagnosis.
1. Clinically VAGUE.
2. TISSUE DIAGNOSIS.
• Delayed Onset of Diagnosis  Advanced Disease.
• Lacking of Response to Available Treatment Options
A HASSLE & WASTE OF RESOURCES
OR
REAL UNDERESTIMATED PROBLEM?

Origin:
Neuropeptides
Catecholamines
Hormonal
Syndromes
Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine
tumors. Endocrinol Metab Clin North Am 2011; 40:1.

2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1983
1982
1981
1980
1979
1978
1977
1976
1975
1974
1973
0.00
1.00
2.00
3.00
4.00
5.00
6.00
0
100
200
300
400
500
600
Incidenceper100,000-NETs
Incidenceper100,000–Allmalignantneoplasms
All malignant neoplasm
Neuroendocrine tumors
Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
Increasing Incidence
Plateau
1.09
5.25

Incidence of NETs Is Increasing*
8 8
SEER = Surveillance, Epidemiology, and End Results (for malignant NETs)
*Approximate 5-fold increase between 1975 and 2004
Approximate 7-fold increase also evident in Norwegian registry
IncidencePer100,000
1.40
Year
NET Site
1.20
1.00
0.80
0.60
0.40
0.20
0
Lung
Colon
Small intestine
Rectum
Pancreas
Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.

Colon Neuroendocrine Stomach
29-year limited duration prevalence analyses based on SEER
Pancreas Esophagus Hepatobiliary
0
100
1,100
NET Prevalence in the US, 2004
1,200
Median survival (1988 –
2004)103,312
cases
(35/100,000)
No.ofcases
(thousands)
Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
NETs Are the 2nd-Most Prevalent
Gastrointestinal Tumor:
• Localized
• Regional
• Distant
203 months
114 months
39 months

NET: Demographics:
Lepage C, et al. Gut. 2004;53(4):549-553.

descendin
g colon
(<1%)
sigmoid
colon (-
12%)
Primary Tumor Localizations
est. % of all NEN
thymus
bronchus
esophagus
stomach
duodenum
pancreas
jejunum/ileum
cecum
appendix
colon
rectum
<1
15
<1
15
4
15
15
2
15
1
10
thymus (1%)
bronchus (-15%)
esophagus (<1%)
pancreas (-15%)
duodenum (-4%)
ascending
colon (-
1%)
jejunum (-5%)
ileum (-10%)
cecum (-2%)
appendix (-15%)
rectum (-10%)
stomach (-15%)
Pape UF, et al. Gastroenterol up2date. 2011;7:313-
339.

Hormone Hypersecretion Syndromes
(= Functioning NET)
Calcitonin
Somatostatinoma
Cushing syndrome
Atypical carcinoid syndrome
Verner Morrison syndrome (VIPom)
Glucagonoma
Gastrinoma
Insulinoma
Carcinoid syndrome
0 20 40 60 80 100 120 140 160 180 200 220 240
244
158
76
16
8
5
6
2
1
Begum N, et al. Zentralbl Chir. 2014;139(3):276-283.
Functioning: 39.5% (553)
Non-functioning: 60.0% (836)
Unclear: 0.5% (11)

NE-cell
Enterocyte
Enterocyte
Enterocyte
Enterocyte
Pathogenesis of Carcinoid:
Rindi G, Wiedenmann
B. Nat Rev Endocrinol.
2011;8(1):54-64

TRYPTOPHAN METABOLISM
NORMAL NET
1%
SEROTONIN
70%
SEROTONIN
FOREGUT MIDGUT HINDGUT
Aromatic L- Amino Acid
Decarboxylase

Marc Díez, Alexandre Teulé, Ramon Salazar.Ann Gastroenterol 2013; 26 (1): 29-36

Somatostatin: The Natural Defense Mechanism:
SOMATOSTATIN
Somatostatin
Receptors
Short Lived Bio-availability

Niederle MD, et al. Endocr Relat Cancer. 2010;17(4):909-918.
Biologicalbehavior
Malignant
Uncertain
Benign
NET: Not all the same:

Key Issues in The Management:
1. How do we define the disease?
Nomenclature, Classification & Pathology.
2. Who needs treatment and when?
Patient Selection.
3. Which treatment and in what sequence?
Treatments.
4. What is the role of combined biologics,
somatostatin analogues, cytotoxics and
biomarkers?
Unanswered Questions.

1.How do we define the disease?
Nomenclature, Classification and
Pathology

Evolution of Terminology & Classification:
Historic Evolution:
1907 1963 1970 1980 1995
Carcinoid
Williams &
Sandler
Soga &
Tazawa
Histologic
WHO
Granular
Stain
Techniques
Capella
Size &
Invasion
• Benign.
• Benign or Low
Grade Malignant.
• Low Grade
Malignant.
• High Grade
Malignant.
No Prognostic or Predictive
Validation

H.E.
MIB-1/Ki67
synaptophysin
CgA
Neuroendocrine Neoplasms

Histopathologic Differentiation:
Well
Differentiated
Poorly
Differentiated

AJCC Criteria of Grading:
Grade Mitotic
Count (per
10 HPF)
Ki 67
Index (%)
G1 < 2 < 2
G2 2 – 20 3 – 20
G3 > 20 > 20
AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.

Correlation of Tumor Grade With Survival:
1. Rindi G, Klöppel G, Alhman H, et al. Virchows Arch. 2006;449:395-401. 2. Rindi G, Klöppel G, Couvelard A, et al.
Virchows Arch. 2007;451:757-762. 3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer. 2008;113:256-265.
0 50 100 150 200 250
Survival Time (mo)
0.0
0.2
0.4
0.6
0.8
1.0
CumulativeSurvival
G1
G2
G3
G1 vs G2
G1 vs G3
G2 vs G3
P=0.040
P<0.001
P<0.001
N=193

Scarpa A, et al. Mod Pathol. 2010;23(6):824-
833.
< 2% 15% 75%
Pape UF, et al. Endocr Relat
Cancer. 2008;15(4):1083-1097.
Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798-
7803. Vilar E, et al. Endocr Relat Cancer. 2007;14(2):221-
232.
Prognostic Influence of Ki67-Labelling

Correlation of TNM Staging With Survival:
26 26
La Rosa S, Klersy C, Uccella S, et al. Hum Pathol.
2009;40:30-40.
Patients With Well-Differentiated Pancreatic NET
Stage I
P<0.001
ProportionAlive
Stage II
Stage III
Stage IV
I (n = 44)
II (n = 44)
III (n = 34)
IV (n = 33)
Time (mo)
0.00
0.25
0.50
0.75
1.00
0 48 96 144 192 240

NETs Are Often Diagnosed Late:
Vinik AI, Silva MP, Woltering EA, et al. Pancreas. 2009;38:876-889.
1 2 3 4 5 6 7 8 9
Time (yr)
Primary tumour growth
Metastases
Flushing
Diarrhea
Death
Vague abdominal symptoms
Estimated time to diagnosis: 5 to 7 yr
*
*
*Symptoms of carcinoid syndrome

Metastatic Disease Is Common at Presentation:
Localized Metastatic
50%
27%
23%
Distant metastases
Regional spread
Data from an analysis of 28,515 cases of NET identified in the SEER registries
Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.
*These data are of the cases in which stage was reported.
20% of cases did not provide disease stage information

Pathology Report of NETs
• Define location and tumor type based on WHO
classification
• Define tumor grade (including Ki-67 proliferative index)
• Describe the presence of additional histologic features
(multicentric disease, non-ischemic tumor necrosis, vascular or
perineural invasion)
• Assess the TNM stage
• Define the resection margins
• Define the hormonal production, if any
• Upon request, assess prognostic or predictive factors
useful for target therapy (eg, somatostatin receptors,
mTOR pathway molecules, other target enzymes, …)
Klimstra D, et al. Am J Surg Pathol. 2010;34(3):300-313.

2. Role of Biomarkers & Imaging:

Pan-neuroendocrine markers
Cytosolic NSE, PGP 9.5
Related to secretory
granules
Chromogranin
Related to synaptic vesicles Synaptophysin, VMAT
Intermediate filaments NF, CK HMW
Adhesion molecules N-CAM
Immunohistochemical NE markers:

 Chromogranin A*
(in 70%-90% increased in metast. NET)
 Pancreatic Polypeptide, PP
(in 40%-55 % elevated);
 a-HCG, β-HCG
(in ~ 30% elevated)
 Neuron specific enolase (NSE)
(in ~33% elevated)
*The height of Chromogranin A level correlates with tumor load,
an increase over time indicates tumor progression
Circulating Tumor Markers:

CgA correlates with hepatic tumor load
Heigher CgA levels indicate lower survival
Arnold R, et al. Clin Gastroenterol Hepatol. 2008;6(7):820-827
Prognostic Value of CgA:

HR = 0.25
95% CI: 0.13-0.51
P = .00004
Median PFS
Early response = 13.3 mos.
No early response = 7.5 mos.
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
HR = 0.25
95% CI: 0.10-0.58
P = .00062
CgA NSE Median PFS
Early response = 8.6 mos.
No early response = 2.9 mos.
PFS(%)
0
20
40
60
80
100
0
20
40
60
80
100
Time Since Study Start, months Time Since Study Start, months
Pts at Risk Pts at Risk
Resp. 33 29 26 19 12 5 3 2 0 Resp. 28 23 16 9 6 3 1 0 0
Nonresp 38 26 12 5 1 1 0 0 0 Nonresp. 11 5 2 0 0 0 0 0 0
Yao JC, et al. J Clin Oncol. 2010;28(1):69-76.
RADIANT-1 (Stratum I)
Predictive Value of Biomarkers:
PFS by Early CgA and NSE Responses:

Modlin IM, et al. Ann Surg Oncol. 2010;17(9):2427-2443.
PPI
Chronic Atrophic
Gastritis
PPI
H2RAs
Small cell lung cancer
Prostate cancer
Breast cancer
Ovary Cancer
Chronic atrophic gastritis
Pancreatitis
Inflammatory bowel disease
Irritable bowel syndrome
Liver cirrhosis
Chronic hepatitis
Colon cancer
HCC
Pancreatic adenocarcinoma
Pheochromocytoma
Hyperparathyroidism
Pituituary tumors
Medullary thyroid carcinoma
Hyperthyroidism
CgA
ENDOCRINE
DISEASE
GASTRO-
INTESTINAL
DISORDERS
NON-GI
CANCER
Arterial hypertension
Cardiac insufficiency
Acute coronary syndrome
Giant cell arteritis
CARDIOVASCULAR
DISEASE
Systemic rheumatoid arthritis
Systemic inflammatory response syndrome
Chronic bronchitis
Airway obstruction in smokers
INFLAMMATORY
DISEASES
Renal Insufficiency
RENAL DISORDERS
DRUGS
Causes of Chromogranin A Elevation:

Diagnosis: Imaging Primary Tumor/Tumor
Spread:
 Whole body Screening
& Staging
 Endocrine Pancreatic tumor
< 1cm
 Routine imaging
 Primary tumour Screening
& Staging (optional)
 Octreoscan (111Indium-DTPA-
Octreotide)/ SPECT: 1. choice
 Endoscopic ultrasonography
 ultrasonography of the liver
 CT (+ angiography), MRI
 Positron emission tomography (PET)
with 11C-5 HTP,11C-L-dopa or 18F-FDG
 SMS-R-PET: 68Gallium-DOTATOC-
PET
 PET/CT
ENETS-Guidelines 2011

3. Therapy for Advanced Disease
“Symptom Control
& Cytotoxic Therapy”

Therapy of NETs
Three principles
• Control of hormonal
symptoms
• Control of tumor
growth
• Improvement of
survival?
Symptomatic
therapy
Surgical
therapy
Antiproliferative
therapy
• Cure
• Debulking
• Treatment /
Prevention of
complications

Resection of primary tumor
in distant metastatic disease?
249 primary resected, MS = 7.4 y
Hellman et al, 2002
Givi et al, 2006
Ahmed et al, 2009
Rinke et al 2009
Resection of primary tumor (intestine) and impact on prognosis

Survival after resection of liver metastases
Consenus Conference, London 2012
Frilling et al, 2014, *Sarmiento et al 2003, Elias et al 2003, Glazer et al 2010, Mayo et al 2010
Limitations
Complete resection in
20–57%
Recurrence in up to 94%
after 5 years*
No randomized trials

Therapy of GEP-NETs: Shifting From
Symptom Management to Targeting Tumors
Somatostatin
analogues
Symptomatic therapy
(carcinoid syndrome)
Control of
tumor growth

Possible Mechanisms for Antiproliferative
Activities of SSAs
Antiproliferative effect of SSA
Direct antiproliferative effect Indirect antiproliferative effect
Binding to the somatostatin
receptor on tumor cells
Systemic effect
Inhibition
of cell
cycle
Inhibition
of growth
factor
effects
Pro-
apoptotic
effect
Inhibition
of growth
factor and
trophic
hormones
Inhibition of
angiogenesis
Immune
system
modulation
Susini C, et al. Ann Oncol. 2006;17(12):1733-1742.

Somatostatin Receptors (SSTR) Are
Expressed by the Majority of NETs
• SSTR2 is most prevalent in GEP-NETs and induces
inhibitory effects on hormone secretion and proliferation
in NETs
• Somatostatin is effective in controlling NET-related
hormonal symptoms
• Clinical use of somatostatin is limited by its short half life
Basu B, et al. Endocr Relat Cancer. 2010;17(1):R75-R90. Modlin IM, et al. Aliment Pharmacol Ther.
2010;31(2):169-188. Hofland LJ. J Endocrinol Invest. 2003;26(8 Suppl):8-13. Ferrante E, et al. Endocr Relat
Cancer. 2006;13(3):955-962.
Prevalence on NET type: SSTR1 SSTR
2
SSTR3 SSTR4 SSTR5
Pancreas 68% 95% 46% 93% 57%
Midgut 80% 86% 65% 35% 75%
Inhibitory effect:
Hormone secretion + + +
Proliferation + + + +
Induction of apoptosis + +

• Octreotide and lanreotide show high affinity for the
SSTR2 and are approved for antisecretory treatment in
NETs
LAR, long lasting release
Susini C, et al. Ann Oncol. 2006;17(12):1733-
1742.
Octreotide LAR
(10-30 mg / 28 days im)
Lanreotide
(60-120 mg / 28 days sc)
Octreotide
(2-3 x 50-500 ug sc / d)
Biotherapy of Functional Active NETs
With Somatostatin Analogs (SSA)
S
S
a
l
a
g
l
y
ly asn
s
cys p
h
e
p
h
e
p
h
e tr
p
l
y
s
t
h
r
p
h
e
t
h
r
s
e
r
cys
D-phe c
y
s
phe
l
y
s
c th
y r
s
Octreotide
acetate
D-trp
Thr
-
ol
D-phe c
l
y
s
v
al
c
y
y
s
S
ty
r
s
Lanreotid
e
D-trp
Thr
-
NH2
S
Somatostatin
S
S

Phase III Study of Octreotide LAR:
PROMID Study:
Patients:
• Well-differentiated
midgut NET
• Treatment-naïve
• Locally inoperable
or metastasized
N = 85
Octreotide LAR
30 mg im/28 days
Placebo
im/28 days
Primary endpoint:
• Median time to tumour progression
Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
1:1
R
A
N
D
O
M
I
Z
E
Secondary endpoints:
•Objective tumour response rate
• Symptom control
• Overall survival
Treatment
until CT/MRI
documented
tumour
progression
or death
Randomized, Double-blind, Placebo-controlled Study

Octreotide LAR 30 mg
Significantly Prolongs TTP:
HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients
with metastatic neuroendocrine MIDgut tumours; TTP = time to progression
Octreotide LAR vs placebo
HR=0.34 P=0.000072
[95% CI: 0.20–0.59]
Based on conservative ITT analysis
ProportionWithout
Progression
1.0
.75
.50
.25
0
0 6 12 18 24 30 36 42
Time (mo)
48 54 60 66 72 78
Octreotide LAR (n = 42)
Median 14.3 mo
Placebo (n = 43)
Median 6.0 mo

Octreotide LAR 30 mg Extends TTP in Patients With
Functioning and Nonfunctioning Tumours:
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
Based on the per-protocol analysis
P=0.0008; HR=0.25 (95% CI: 0.10–0.59)
ProportionWithoutProgression
P=0.0007; HR=0.23 (95% CI: 0.09–0.57)
ProportionWithoutProgression
Patients with nonfunctioning tumours Patients with functioning tumours
Time (mo)Time (mo)
Octreotide LAR 30 mg: 17 pts/11 events
Median TTP 14.26 mo
Placebo: 16 pts/14 events
Median TTP 5.45 mo
Octreotide LAR 30 mg: 25 pts/9 events
Median TTP 28.8 mo
Placebo: 27 pts/24 events
Median TTP 5.91 mo
1. Arnold R, Müller H, Schade-Brittinger C, et al. J Clin Oncol. 2009;27(suppl):15s. Abstr 4508.
2. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.

Octreotide
LAR (n=42)
Placebo
(n=43)
Complete response (n) 0 0
Partial response (n) 1 1
Stable disease (n) 28 16
Progressive disease (n) 10 23
Unknown (n) 3 3
Wilcoxon-Mann-Whitney: P=0.0079
Octreotide LAR Achieved Superior Tumor
Response at 6 Months (WHO):

The PROMID Study: Octreotide LAR in
Midgut NETs – What Did We Learn?
Lessons Limitations
Rinke A, et al. J Clin Oncol. 2009;27(28): 4656-4663.
Octreotide LAR shows
antitumor effect in:
• Midgut tumors
• Low hepatic tumor
burden (<10%)
• Grade 1 tumors
The efficacy of SSAs is
uncertain in:
• Non-midgut tumors
• Higher liver tumor
burden (<10%)
• Grade 2 tumors
• Progressive disease
Would an antiproliferative effect be replicable, with lanreotide,
in a larger and more advanced population with GEP-NETs?

Lanreotide Acetate in NET:
• Patient Characteristics: Clarinet Trial:
• Well to Moderately differentiated.
• Ki 67 < 10%
• Pancreas, mid-gut, hind-gut, or Unknown origin.
N Engl J Med 2014;371:224-33.

The SYM-NET StudyDESIGNASSESSMENTS
A non-interventional cross sectional study to assess SYMptom
control in neuroendocrine tumors (NET)
Non-interventional, cross-sectional study
273 patients suffering from NET, already treated with lanreotide for at least 3
months and with history of diarrhea due to carcinoid syndrome were
enrolled
Subject questionnaires
Investigator review
of medical record
Likert scales
• Patient satisfaction
• Symptom severity
• Perception change
diarrhea
• Feelings about conse-
quences on daily life
QoL
• EORTC C30
• EORTC GI-
NET21
Demography
Medical
history
Treatment with
lanreotide
Diarrhea
Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ
characteristics
• At Tt initiation
• Day of visit
Other clinical
data
• At Tt initiation
• Day of visit
Qol = quality of life

SYM-NET Study – Results and Conclusion
Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract
411ˆ
• An improvement was observed for the majority
of patients in all symptoms
– 76 % patient satisfaction with diarrhea control (primary
objective)
– 73 % patient satisfaction with flushing control
– QoL questionnaires showed a high level of activity
capacity and low symptoms score
• Patient-reported "subjective" information was
consistent with investigator’s observation
• Confirms in real life setting the satisfactory effect
of lanreotide on symptoms of hormonal excess in
GEP- NETs

Symptom relief in carcinoid syndrome
by Somatostatin analogsSymptomaticresponse(%)
0
25
50
75
100
Octreotide Octreotide LAR Lanreotide Lanreotide slow
release / autogel
Mean: 74.2
Median: 71
Mean: 77.3
Median: 75
mean: 63.0
median: 63
mean: 67.5
median: 63
Modlin IM, et al. Alimentary Pharmacol Ther. 2010;31:169-88.
Studies (n) 11 7 1 7
Patients (n) 261 122 30 185

Objective response rate: <20 %
n = 367
STZ, streptozotocin; 5FU, 5-flurouracil; DOX, doxorubicin
Moertel CG, et al. Cancer Clin Trials. 1979;2(4):327-334. Engstrom PF, et al. J Clin Oncol. 1984;2(11):1255-1259.
Bukowski RM, et al. Cancer. 1987;60(12):2891-2895. Sun W, et al. J Clin Oncol. 2005;23(22):4897-4904. Öberg K,
et al. Ann Oncol. 2010;21:v223–v227.
Chemotherapy Is Not Effective in NETs
Grade 1/ Grade 2 of the Midgut (Carcinoids)
Reference Type of
tumor
Regimen No. of
patients
Objective
response
Response
duration
(months)
Median
survival
(months
)
Moertel and Carcinoids 5FU + cyclophosphamide 47 33 – –
Hanley STZ + 5FU 42 33 – –
Engstrom et al Carcinoids STZ + 5FU 80 22 8 16
DOX 81 21 6.5 12
Bukowski et al Carcinoids STZ + DOX + 5FU +
cyclophosphamide
STZ + 5FU +
56
9
31
22
–
–
–
10.8
cyclophosphamide
Sun et al Carcinoids DOX + 5FU 25 15.9 4.5 15.7
STZ + 5FU 27 16 5.3 24.3

Chemotherapy for G3 NET: NORDIC Trial:
Annals of Oncology 24: 152–160, 2013

Temozolomide in Pancreatic
Neuroendocrine Carcinoma
Strosberg JR, et al. Cancer 2011;117(2):268-275
Capecitabine
Temozolomide
every 28 days
750 mg/m2 x 2 x tgl. (days 1–
14)
200 mg/m2 x 1 (days 10–14);
n = 30: 22 NF; 2 gastrinoma; 2 insulinoma; 2 VIPoma; 1
glucagonoma;
1 gastrinoma/glucagonoma
70% PR
(RECIST
)
Median
PFS: 18
months
Retrospective analysis
G3–4 adverse events (12%): anemia, thrombocytopenia, elevation of liver
enzymes
100
80
60
40
20
0
–20
–40
–60
–80
–100
Progressive
Disease
Partial Response

Streptozocin/5-Fu are RE-EMPOWERED
in 2015:

in 2015: RR & Treatment Outcome:

in 2015: Which Subset Got Benefit?

4. Molecular Events &Targeted Therapies.

Molecular Events & Therapeutic Implications:
1. Angiogenesis:
vHL Gene OxygenationHypoxia
+++ VEGFAngiogenesis
PFS 96% 68%
Bevacizumab
+ Octreotid LAR
INF
+ Octreotid LAR
Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, Hess K, Ng C, Abbruzzese JL,
Ajani JA. J Clin Oncol. 2008;26(8):1316.

Molecular Events & Therapeutic Implications:
2. mTOR Pathway:
Mammalian Target of Rapamycin
mTORC1 mTORC2
Protein
Synthesis
Cell Growth Autophagy
Altered
Metabolism
Increased
Proliferation
Apoptosis
Resistance
+++
+++
RTK
AKT
PI3K
RAS –RAF
MEK

Targeted Drugs
in Neuroendocrine Tumors
 Novel Somatostatin analogues:
Pasireotide (SOM230), chimeric molecules (e.g. Dopastatin)
 Others: Tryptophan hydroxylase inhibitor (Telotristat Etiprate,
LX1606), IGF-1 R antagonists/ antibodies, HDAC inhibitors etc
 Angiogenesis inhibitors:
VEGF-Receptor-Tyrosinkinase-Inhibitor PTK787/ZK,
Anti-VEGF (Bevacizumab), Endostatin, Thalidomide
 Single / multiple tyrosine kinase inhibitors:
Imatinib, Gefitinib, Sorafenib, Sunitinib
 mTOR Inhibitors: Temsirolimus, Everolimus

Everolimus 10 mg/d +
best supportive care1
n = 207
RADIANT-3: Study Design
Placebo +
best supportive care1
n = 203
Multiphasic CT or MRI performed every 12 weeks
Treatment
until disease
progression
Patients with
advanced
pNET,
N = 410
Stratified by:
• WHO PS
• Prior chemotherapy
Crossover
1:1
R
A
N
D
O
M
I
S
E
Phase III, Double-Blind, Placebo-Controlled Trial
Primary Endpoint: PFS
Secondary Endpoints: OS, ORR, biomarkers, safety, pharmacokinetics
(PK)
Yao J, Shah M, Ito T, et al. N Engl J Med. 2011;364:514-523.
1:1

RADIANT-3: Baseline Characteristics
Everolimus (n = 207) Placebo (n = 203)
Median age, years (range) 58 (23-87) 57 (20-82)
Male : Female (%) 53 : 47 58 : 42
WHO PS (%)
0 / 1 / 2 67 / 30 / 3 66 / 32 / 3
No. of disease sites(%)
1 25 31
2 41 32
≥3 34 38
Histologic Grade (%)
Well differentiated 82 84
Moderately differentiated 17 15
Unknown 1 1
Prior Treatment (%)
Somtatostatin analogues 49 50
Chemotherapy 50 50
Radiotherapy 23 20
Yao J, Shah M, Ito T, et al. N Engl J Med. 2011;364:514-523.

RADIANT-3
PFS by Investigator Review:
• P value obtained from stratified 1-sided log-rank test
• Hazard ratio is obtained from stratified unadjusted Cox model
%Event-free
0 2 4 6 8 10
No. of patients still at risk
Kaplan-Meier median PFS
Everolimus:
Placebo:
11.0 mo
4.6 mo
Hazard ratio = 0.35; 95% CI 0.27–0.45
P value: <.0001
PFS rate (18 mos.)
Everolimus 34.2%
Placebo 8.9%
Yao JC, et al. N Engl J Med. 2011;364(6):514-
523.
12 14 16 18
Time (mo)
100
80
Censoring times Everolimus
(n/N = 109/207) Placebo
(n/N = 165/203)
60
40
20
0
20 22 24 26 28 30

• Everolimus toxicities were similar to those seen in other tumour
types
• Most frequently reported all-grade treatment-related AEs with
everolimus were stomatitis (64%), rash (49%), diarrhea (34%),
fatigue (31%), and infections (23%)
• Grade 3/4 AEs (≥5%) in the everolimus arm included stomatitis
(7%), anemia (6%), and hyperglycemia (5%)
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
RADIANT-3:
Treatment-Related Adverse Events

RADIANT-3: Summary
• Everolimus therapy resulted in a statistically and clinically significant
6.4-month increase in median PFS (4.6 months to 11.0 months)
• Everolimus provided a 65% reduction in risk for progression
compared to placebo (HR = 0.35, P<.0001)
• PFS rate at 18 months: 34% everolimus versus 9% placebo
demonstrates that everolimus provides a durable benefit
• Everolimus has an acceptable safety profile in patients with advanced
pNET

RADIANT-2 Study Design:
Everolimus 10 mg/day +
Octreotide LAR 30 mg/28 days
n = 216
Placebo +
Octreotide LAR 30 mg/28 days
n = 213
Treatment
until disease
progression
R
A
N
D
O
M
I
Z
E
1:1
Multiphasic CT or MRI performed every 12 wk
Crossover
Primary endpoint:
• PFS (RECIST)
Secondary endpoints:
• Tumour response, OS, biomarkers, safety, PK
Enrollment January 2007–May 2008
Phase III, Double-blind, Placebo-controlled Trial
Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
Patients with advanced NET
(N=429)
• Advanced low- or intermediate-
grade NET
• Radiologic progression <12
months
• History of secretory symptoms
(flushing, diarrhea)
• Prior antitumour therapy allowed
• WHO PS ≤2

PFS by Central Review:*
Time (mo)
E + O
P + O
216
213
202
202
167
155
129
117
120
106
102
84
81
72
69
65
63
57
56
50
50
42
42
35
33
24
22
18
17
11
11
9
4
3
1
1
1
0
0
0
* Independent adjudicated central review committee
• P-value is obtained from 1-sided log-rank test
• HR is obtained from unadjusted Cox model
E + O = everolimus + octreotide LAR
P + O = placebo + octreotide LAR
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
PercentageEvent-free
Everolimus + octreotide LAR: 16.4 mo
Placebo + octreotide LAR: 11.3 mo
HR = 0.77; 95% CI (0.59–1.00)
P=0.026
Total events = 223
Censoring times
E + O (n/N = 103/216)
P + O (n/N = 120/213)

Subgroup PFS Analysis:
*Independent adjudicated central review
HR = everolimus + octreotide/placebo + octreotide
Unstratified Cox model was used to obtain HR
E + O = everolimus + octreotide LAR
P + O = placebo + octreotide LAR
Subgroups (N)
Central review *(429)
Local investigator review (429)
Age group
<65 yr (286)
≥65 yr (143)
Gender
Male (221)
Female (208)
WHO Performance Status
WHO = 0 (251)
WHO > 0 (176)
Tumour histology grade
Well-diff. (341)
Moderately diff. (68)
Primary tumour site
Small intestine (224)
Lung (44)
Colon (28)
Other (132)
Prior long-acting SSA
Yes (339)
No (90)
Prior chemotherapy
Yes (130)
No (299)
HR
Median PFS
(mo)
E + O P + O
0.77 16.4 11.3
0.78 12.0 8.6
0.78 19.2 13.0
0.75 13.9 11.0
0.85 13.7 13.0
0.73 17.1 11.1
0.67 21.8 13.9
0.81 13.6 8.3
0.74 18.3 13.0
0.82 13.7 7.5
0.77 18.6 14.0
0.72 13.6 5.6
0.39 29.9 13.0
0.77 14.2 11.0
0.81 14.3 11.1
0.63 25.2 13.6
0.70 13.9 8.7
0.78 19.2 12.0
Hazard Ratio
Favors E + O Favors P + O
0 10.4 0.8 1.4

Everolimus: Real World Trial:
• Med PFS = 12 months
• Med OAS = 32 months
• Pancreatic = Non Pancreatic

RADIANT-4 Study Design
*Based on prognostic level, grouped as: Stratum A (better prognosis)  appendix, caecum, jejunum,
ileum, duodenum, and NET of unknown primary. Stratum B (worse prognosis)  lung, stomach,
rectum, and colon except caecum.
Crossover to open label everolimus after progression in the placebo arm was not allowed prior to the
primary analysis.
Endpoints:
• Primary: PFS (central)
• Key Secondary: OS
• Secondary: ORR, DCR, safety, HRQoL
(FACT-G), WHO PS, NSE/CgA, PK
Patients with well-
differentiated (G1/G2),
advanced, progressive,
nonfunctional NET of lung
or GI origin (N = 302)
• Absence of active or any
history of carcinoid
syndrome
• Pathologically confirmed
advanced disease
• Enrolled within 6 months
from radiologic progression
Everolimus 10 mg/day
N = 205
Treated until PD,
intolerable AE, or
consent withdrawal
2:1
R
A
N
D
O
M
I
Z
E
Placebo
N = 97
Stratified by:
• Prior SSA treatment (yes vs. no)
• Tumor origin (stratum A vs. B)*
• WHO PS (0 vs. 1)

Characteristic
Everolimus
N = 205
Placebo
N = 97
Age, median (range) 65 (22 – 86) 60 (24 – 83)
Male / female 43% / 57% 55% / 45%
WHO performance status
0 / 1 73% / 27% 75% / 25%
Race
Caucasian 79% 70%
Asian 16% 19%
Other* 5% 11%
Primary tumor site
Lung 31% 28%
Ileum 23% 25%
Rectum 12% 16%
Jejunum 8% 6%
Stomach 3% 4%
Duodenum 4% 2%
Colon 2% 3%
NET of unknown primary 11% 13%
Baseline and Disease Characteristics (1/2)
*Included Black.

Characteristic
Everolimus
N = 205
Placebo
N = 97
Tumor grade
Grade 1 / grade 2 63% / 37% 67% / 33%
Metastatic extent of disease†
Liver 80% 78%
Lymph node or lymphatic system 42% 46%
Lung 22% 21%
Bone 21% 16%
Median time from initial diagnosis to
randomization, months (range)
29.9 (0.7-258.4) 28.9 (1.1-303.3)
Median time from most recent progression until
enrolment, months (range)‡ 1.68 (0.0-7.8) 1.45 (0.2-11.8)
Prior treatments
Somatostatin analogues 53% 56%
Surgery 59% 72%
Chemotherapy 26% 24%
Radiotherapy including PRRT 22% 20%
Locoregional and ablative therapies 11% 10%
†Organs as per target and non-target lesion locations observed at baseline by central radiology review.
‡Patients were expected to have disease progression in ≤ 6 months prior to enrolment as per inclusion criteria. Protocol deviation
was reported in 7 patients.
Baseline and Disease Characteristics (2/2)

Primary Endpoint: PFS by Central Review
52% reduction in the relative risk of progression or death with
everolimus vs placebo
HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001
P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.
205 168 145 124 101 81 65 52 26 10 3 0 0
97 65 39 30 24 21 17 15 11 6 5 1 0Placebo
Everolimus
No.of patients still at risk
0 2 4 6 8 10 12 15 18 21 24 27 30
Months
0
10
20
30
40
50
60
70
80
90
100
ProbabilityofProgression-freeSurvival(%)
Kaplan-Meier medians
Everolimus: 11.0 months (95% CI, 9.23-13.31)
Placebo: 3.9 months (95% CI, 3.58-7.43)
Censoring Times
Everolimus (n/N = 113/205)
Placebo (n/N = 65/97)

Consistent Investigator-Assessed PFS
Everolimus vs Placebo
HR = 0.39 (95% CI, 0.28-0.54); P < 0.00001
205 171 148 132 108 93 75 59 33 15 5 0
97 70 47 35 27 25 21 19 10 6 4 0Placebo
Everolimus
Time (Months)
0
10
20
30
40
50
60
70
80
90
100
ProbabilityofProgression-freeSurvival(%)
No.of patients still at risk
Kaplan-Meier medians
Everolimus: 14.0 months (95% CI, 11.24-17.71)
Placebo: 5.5 months (95% CI, 3.71-7.39)
Censoring Times
2 4 6 8 10 12 15 18 21 24 270 30
0
0

Consistent PFS HR by Stratification Factors, Central
Review
Hazard ratio obtained from unstratified Cox model.
NET, neuroendocrine tumors; SSA, somatostatin analogues; WHO PS, World Health Organization performance status.
Prior SSA treatment
Yes
No
Tumor origin*
Stratum A
Stratum B
WHO PS
0
1
157
145
153
149
216
86
Hazard Ratio (95% CI)No.Subgroups
0.52 (0.34-0.81)
0.60 (0.39-0.94)
0.63 (0.40-1.02)
0.43 (0.28-0.66)
0.58 (0.41-0.84)
0.50 (0.28-0.91)
0.1 0.4 1 10
Everolimus Better Placebo Better
*Based on prognostic level, grouped as: Stratum A (better prognosis) - appendix, caecum, jejunum,
ileum, duodenum, and NET of unknown primary). Stratum B (worse prognosis) - lung, stomach, rectum,
and colon except caecum).

PFS HR by Primary Liver Tumor Burden, Central
Review
Hazard ratio obtained from unstratified Cox model.
None
≤10%
>10%-25%
>25%
Hazard Ratio (95% CI)Liver Tumor Burden
48
180
37
35
No.
0.49 (0.20-1.20)
0.67 (0.45-1.00)
0.62 (0.20-1.93)
0.18 (0.06-0.50)
0.1 0.4 1 10
Everolimus Better Placebo Better

Interim Overall SurvivalAnalysis
*P-value boundary for significance = 0.0002.
NS, not significant.
205 195 184 179 172 170 158 143 100 59 31 5 0
97 94 86 80 75 70 67 61 42 21 13 5 0Placebo
Everolimus
0 2 4 6 8 10 12 15 18 21 24 27 30
Months
0
10
20
30
40
50
60
70
80
90
100
ProbabilityofOverallSurvival(%)
Censoring Times
Everolimus vs Placebo
HR = 0.64 (95% CI, 0.40-1.05); P = 0.037 (NS)*
First interim OS analysis performed with 37% of information fraction
favored the everolimus arm
Next interim analysis is
expected in 2016

Best Overall Response and
Tumor Shrinkage, Central Review
100
75
50
25
0
25
50
75
100
Best%ChangefromBaseline
inSizeofTargetLesions
Everolimus Placebo
Increase in tumor size as best response Decrease in tumor size as best response
100
75
50
25
0
25
50
75
100
************** *************
Best Overall Response
Everolimus
N = 205, n (%)
Placebo
N = 97, n (%)
ORR (CR + PR) 4 (2.0) 1 (1.0)
DCR (CR + PR + SD) 169 (82.4) 63 (64.9)
PD 19 (9.3) 26 (26.8)
Unknown 17 (8.3) 8 (8.2)
64% of patients receiving everolimus had any degree of tumor shrinkage
vs 26% receiving placebo
*Fourteen patients (7.6%) in the everolimus arm and 13 patients (15.3%) in the placebo arm showed a change in the available target
lesion that contradicted the overall response.
CR, complete response; DCR, disease control rate; ORR, overall response rate; PD, progressive disease; PR, partial response;
SD, stable disease.

AEs Consistent with Known Safety Profile of
Everolimus
Everolimus
N = 202
Placebo
N = 98
Drug-related adverse events All grades Grade 3/4 All grades Grade 3/4
Stomatitis* 63% 9% 19% 0
Diarrhea 31% 7% 16% 2%
Fatigue 31% 3% 24% 1%
Infections† 29% 7% 4% 0
Rash 27% 1% 8% 0
Peripheral edema 26% 2% 4% 1%
Nausea 17% 1% 10% 0
Anemia 16% 4% 2% 1%
Decreased appetite 16% 1% 6% 0
Asthenia 16% 1% 5% 0
Non-infectious pneumonitis‡ 16% 1% 1% 0
Dysgeusia 15% 1% 4% 0
Cough 13% 0 3% 0
Pruritus 13% 1% 4% 0
Pyrexia 11% 2% 5% 0
Dyspnea 10% 1% 4% 1%
Hyperglycemia 10% 3% 2% 0
Presented are drug-related adverse events in ≥10% of patients (safety set).
*Includes stomatitis, aphthous stomatitis, mouth ulceration, and tongue ulceration.
†Includes all infections.
‡Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis.

Deaths (Safety Set)
Everolimus
N = 202
Placebo
N = 98
All deaths, n (%) 41* (20.3) 28 (28.6)
On-treatment deaths,† n (%) 7 (3.5) 3 (3.1)
Due to Study indication, n (%) 4 (2.0) 1 (1.0)
Other reasons, n (%) 3 (1.5) 2 (2.0)
Cardiac failure 1 (0.5) 0
Septic shock 1 (0.5) 0
Lung infection 0 1 (1.0)
Respiratory failure 1 (0.5) 0
Dyspnea‡ 0 1 (1.0)
*Does not include one patient randomized to everolimus arm who was never treated and died
†On-treatment deaths are deaths which occurred up to 30 days after the discontinuation of study treatment.
‡Occurred in a 75-year-old female on placebo arm, suspected to be treatment related. Death was preceded with thoracocentesis
for pleural effusion related to disease progression, followed by clinical and hematological signs of infection (most probably pleurisy
with septic shock).

8888
Sunitinib vs Placebo in Advanced pNET:
• Phase III randomized, placebo-controlled, double-blind trial
• Trial stopped after early unplanned analysis showed efficacy and safety
benefit
Primary Endpoint: PFS
Secondary Endpoints: OS, ORR, TTR, duration of response, safety, and patient-reported
outcomes
Patients with
advanced pNET,
N = 171/340
patients enrolled
Sunitinib 37.5 mg/day orally
Continuous daily dosing*
n = 86
Placebo*
n = 85
*With best supportive care
Somatostatin analogues were permitted
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
1:1
R
A
N
D
O
M
I
Z
E

89 89
0.8
0.6
0.4
0.2
0
1.0
ProportionofPatients
5 10 15 20 250
Sunitinib
39 19 4 0 086Sunitinib
28 7 2 1 085Placebo
Number at risk
Time (mo)
Placebo
Sunitinib: 11.4 mo
Placebo: 5.5 mo
HR = 0.42 (95% CI, 0.26–0.66)
P<0.001
Progression-free Survival:*
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
* Local review

1.0
Objective
response: Stable
disease: Median
survival:
34%
5%
94.6
months
Open phase II study, 1,109 patients
with progressive NET (within 12
months), 2,472 cycles 90Y-DOTA-
TOC-therapy, median follow up 23
months
• Objective response rates 30% - 40%
• Survival benefit in responders likely
• Limitations: safety concerns (renal, bone marrow
toxicity), limited availability, lacking randomized studies
0 2 4 6 8 10 12
Time Since Start of Treatment, years
14
0.2
0.4
0.6
0.8
OverallSurvival,probability
Imhof A, et al. J Clin Oncol. 2011;29(17):2416-1423.
No. of
patient
s
No. of
deaths
Median
survival
Hazard
ratio
P
Disease
control
671 280 3.8 years 0.41 vs
progress
<.001
Progress 438 211 1.4 years
PRRT:

Pazopanib in NET:
• 52 patients with G 1 – 2 NET.
• 32 patients with Pancreatic NET.
• 20 patients with Carcinoid Tumors.
• Pazopanib 800 mg daily + Octreotid
Depot till progression or 12 months of
therapy.
Alexandria T Phan* et al. Lancet Oncol 2015; 16: 695–703
21.9%
0%

Pazopanib in NET:
Alexandria T Phan* et al. Lancet Oncol 2015; 16: 695–703
14.4 ms
12.2 ms
25 ms
18.5 ms

TAKE HOME MESSAGE:
• NENs are heterogeneous, and we need to
deal with hormone release, tumor growth
rate and related symptoms
• A different staging classification to other solid
tumors is used for NENs, joining TNM and grading
systems
• SSAs are the cornerstone of therapy for
hormone- related symptoms and recently
showed their antiproliferative effect in G1/Low G2
enteropancreatic NETs
• Better knowledge of molecular biology has
prompted the development of targeted therapies for
NETs, that should be integrated with SSAs,
chemotherapy, PRRT and locoregional therapies

Neuroendocrine Tumors in 2016

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