Professor Barbro Eriksson Department of Endocrine Oncology … · 2013. 7. 9. · Department of Endocrine Oncology ENETS Centre of Excellence Uppsala University Hospital . Diagnostic

Professor

Barbro Eriksson

Department of Endocrine

Oncology

ENETS Centre of Excellence

Uppsala University Hospital

Diagnostic Challenges in NET

• Heterogeneous group of tumours

• Wide variety of clinical presentations

• Late presentation

• Different terminology and classifications

• Histologic diagnosis may be difficult

NET Vary by Primary Tumour Site

• Generally characterized by their ability to produce peptides that may lead to associated syndromes1,2

• Historically classified based on embryonic origin3

– Foregut tumours

– Midgut tumours

– Hindgut tumours

• Today, primary tumour location is recommended for NET classification4

• “Karzinoide”, Oberndorfer 1907

1Modlin IM, et al. Lancet Oncol. 2008;9:61-72. 2Modlin IM, et al. Gastroenterology. 2005;128:1717-1751. 3NCCN. In: Practice Guidelines in Oncology. V.1.2008. 4Klimstra DS, et al. Am J Surg Pathol. 2010;34:300-313.

Foregut

• Thymus

• Esophagus

• Lung

• Stomach

• Pancreas

• Duodenum

Midgut

• Appendix

• Ileum

• Cecum

• Ascending colon

Hindgut

• Distal large bowel

• Rectum

Carcinoid syndrome

flushing ( specific triggers)

diarrhoea

right-sided heart failure

bronchoconstriction

Clinical syndromes associated with

endocrine pancreatic tumours

Functioning (70 30%)

insulinoma 1-3 per million (17%)

gastrinoma 0.5-3 per million (15%)

VIP-oma 0.05-0.2 per million (2%)

glucagonoma 0.01-0.1 per million (1%)

somatostatinoma

ACTH-oma, GRF-oma <10%

calcitonin-, serotonin-

PTH-rp producing

Non-functioning (30 70%) 0.2-2 per million

Classification of NET

• Functional versus non-functional

• Classification by site of origin – Nearly identical characteristics on routine histologic evaluation,

but different responses to therapeutic agents

• Classification by tumour stage: TNM – AJCC

– ENETS

• Histologic classification – Well differentiated, poorly differentiated

– Tumours with a high grade (grade 3), a mitotic count >20 per10

high powered fields, or a Ki-67 proliferation index of >20%

represent highly aggressive malignancies

• Molecular Classification – MEN 1 & 2, Tuberosis Sclerosis, Von Hippel Lindau disease

Incidence of NET is Increasing*

SEER = Surveillance, Epidemiology, and End Results (for malignant NET)

*Approximate 5-fold increase between 1975 and 2004

Approximate 7-fold increase also evident in Norwegian registry

Incid

ence p

er

100,0

00

1.40

Year

1.20

1.00

0.80

0.60

0.40

0.20

0

NET Site

Lung

Colon

Small intestine

Rectum

Pancreas

Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

NET are the Second Most Prevalent

Type of Gastrointestinal Malignancy

1National Cancer Institute. SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/csr/1975_2004; 2Modlin IM, Lye KD, Kidd M. Cancer. 2003;97(4):934-959.

Colorectal1 Stomach1 Pancreas1 Esophagus1 Hepatobiliary1 GEP-NET2

100, 000

Prevalence in SEER Database

1,100, 000

1,200, 000

0

2 times more prevalent than pancreatic cancer

GEP = gastroenteropancreatic

33-Month Median Survival for

Patients with Metastatic NET

Tumours with well- and moderately differentiated histology1

1Yao J, et al. J Clin Oncol. 2008;26:3063-3072; 2Jemal A, et al. CA Cancer J Clin. 2010;60:277-300.

CI = confidence interval

Time (months)

Surv

ival pro

babili

ty

0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72 84 96 108 120

Median survival

Stage Month 95% CI

Localized 223 208-238

Regional 111 104-118

Distant 33 31-35

SEER: 5-year survival, SI-

NET: 54%; pNET 27%

Survival rates are 3 times

higher in specialized centres

in Europe and US

Bosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.

WHO Classifications of

Neuroendocrine Neoplasms of

the GEP System

WHO 2000 WHO 2010

Well-differentiated endocrine tumour (WDET)

Well-differentiated endocrine carcinoma (WDEC)

Poorly differentiated endocrine carinoma/small-cell carcinoma (PDEC)

Neuroendocrine tumours Grade 1 Grade 2

Neuroendocrine carcinoma Grade 3

Mixed exocrine-endocrine carcinoma (MEEC)

Mixed adenoneuroendocrine carcinoma (MANEC)

Tumour-like lesions (TLL) Hyperplastic and preneoplastic lesions

ENETS/AJCC Grading System

ENET/AJCC

Grade Mitotic count (10 HPF)* Ki-67 index (%)**

G1 <2 ≤2

G2 2-20 3-20

G3 >20 >20

1Rindi G, et al. Virchows Arch. 2006;449:395-401. 2Rindi G, et al. Virchows Arch. 2007;451:757-762. 3American Joint Committee On Cancer. AJCC Cancer Staging System. 7th ed.

*10 HPF (high power field) = 2 mm2, at least 40 fields (at 40× magnification) evaluated in areas of highest mitotic density.

** MIB1 antibody; % of 2,000 tumour cells in areas of highest nuclear labeling.

ENETS/AJCC TNM Staging Systems

ENETS = European Neuroendocrine Tumour Society

AJCC = American Joint Committee on Cancer

ENET/AJCC Classification Criteria – GI NET

Stage includes tumour location, size, lymph node involvement/distant metastasis

Stage I T1 N0 M0

Stage IIa T2 N0 M0

Stage IIb T3 N0 M0

Stage IIIa T4 N0 M0

Stage IIIb Any T N1 M0

Stage IV Any T Any N M1

1Rindi G, et al. Virchows Arch. 2006;449:395-401. 2Rindi G, et al. Virchows Arch. 2007;451:757-762. 3American Joint Committee On Cancer. AJCC Cancer Staging System. 7th ed. 4 Rindi et al, JNCI, 2012

Correlation of Tumour Grade and

Cumulative Survival (ENETS Grading

Proposal)

Pape UF, et al. Cancer. 2008;113:256-265.

1ENETS grading system. 210 HPF = 2 mm2 at least 40 fields (40 × magnification) evaluated in areas of highest mitotic density. 3Percentage of 2,000 tumour cells in areas of highest nuclear labeling with MIB1 antibody.

Grade1 Mitotic count (10 HPF)2

Ki-67 index (%)3

G1 2 ≤2

G2 2-20 3-20

G3 20 20 0.2

0 50 100 150 200 250

Time (months)

0.0

0.4

0.6

0.8

1.0

Cu

mu

lative

su

rviv

al

G1

G2

G3

G1 vs G2

G1 vs G3

G2 vs G3

P = .040

P .001

P .001

Biomarkers in NET

• CgA is the best available biomarker for diagnosis of NET – Elevated CgA may correlate with tumour progression

– CgA is elevated 80% to 100% of the time

• NSE is also expressed in NET – Not as commonly used as CgA

– Also elevated in pNET and poorly differentiated NEC

• 5-HIAA reflects serotonin levels – Elevated serotonin levels over time lead to

comorbidities such as cardiac disease

• Specific markers for different syndromes

• New biomarkers in NET are needed to provide better diagnostic and prognostic information

CgA = Chromogranin A; 5-HIAA = 5-hydroxy-3-indoleacetic acid, 5-HT = serotonin, NSE = neuron-specific enolase,

VIP = vasoactive intestinal peptide; SSTR = somatostatin receptor

Vinik A, et al. Pancreas. 2009;38:876-889.

CgA

NSE

VIP

Glucagon

5-HIAA 5-HT

Gastrin

Insulin

SSTR

Radiological Techniques

CT/MRI/US – diagnosis and 60-95% of metastases

follow-up 50-70% of primary tumours

Endoscopic ultrasonography 75-90%

Intraoperative ultrasonography >90%

Rarely angiography

Functional techniques

OctreoScan (somatostatin receptor

scintigraphy [SRS])

Metaiodobenzylguanidine (MIBG)-

scintigraphy

Positron emission tomography (PET )

(11C-5-HTP, 18F-DOPA, 68Ga-DOTA-

octreotide, 68Ga-exendin 4)

Somatostatin receptor imaging can

be used to detect metastatic disease

>80% of neuroendocrine tumours contain high

concentrations of somatostatin receptors (sst1-5)1

Somatostatin receptors can be imaged with a

radiolabelled somatostatin analog – octreotide

(OctreoscanTM)1; PET with 68Ga-labeled somatostatin

analogues

Somatostatin receptor imaging can be used for:2

– Detecting, localizing and staging neuroendocrine

tumours and metastases

– Predicting clinical response to somatostatin analog

therapy

– Selecting patients for peptide receptor radionuclide

therapy 1. Kulke MH. Endocri Relat Cancer 2007;14:207–219

2. Kwekkeboom DJ, et al. Neuroendocrinology 2009;90:184–189

PET/CT with 68Ga-DOTA-octreotide

Hofmann et al, Eur J Nucl Med 2001: Biokinetics and imaging with

somatostatin PET radioligand 68Ga-DOTATOC: preliminary data

Whole body FDG-PET

Frontal projection

Transaxial

Sagittal

in poorly differentiated neuroendocrine tumours

Binderup T et al, JNM, 2010

Neuroendocrine tumours

Tumour biology - Histopathology

Chromogranin A

Synaptophysin

NSE

Specific markers - gastrin, serotonin

Proliferation marker (Ki-67)

Adhesion molecules (CD44 exon v6, v9)

Angiogenic factors (VEGF, bFGF, TGF )

Somatostatin receptors (SSTR 1-5)

Treatment Considerations

Primary tumour

location

Stage and Extent

of disease

Pathology

(grade/rate of

growth)

Functionality

Performance

status

Availability of

treatment

Therapeutic Options for Patients

with Advanced NET

Surgery

– curative or ablative

Debulking

– radiofrequency ablation (RFA)

– embolisation/chemo-/radio

Medical therapy

– chemotherapy

– biological treatment:

• somatostatin analogs

• alpha interferon

• m-TOR inhibitors

• VEGF-R inhibitors

• other TKI’s

Irradiation

– external (bone, brain metastases)

– tumour targeted, radioactive treatment (90Y-DOTATOC,

177Lu-DOTATE)

Chemotherapy for NET

• Streptozotocin, a chemotherapeutic agent,

approved in some countries (US, France) for

pancreatic NET (pNET), however, it is not

effective in the treatment of GI-NET

• Most recent reports of outcome with STZ/Dox or

STZ/5-FU describe PR (WHO, RECIST) of 36-

39% with median duration of 9.3, PFS 18

months, SD 50%; first-line in G2

• Toxicity; gastro-intestinal (grade 1-2), renal

(mainly grades 1-2, grade 3: 8%, grade 4: 0%)

with appropriate monitoring and dose

adjustments Kouvaraki, J Clin Oncol, 2004

Chemotherapy: Temozolomide

Ekeblad; Clin Cancer Res 2007

– 36 patients (35 foregut: 12 EPT, 12 bronchial 7 thymus)

– median 2.4 prior antitumour medical therapies

– RR 14% (40% in low MGMT)

– TTP 7 months

Kulke; ASCO 2006 abstract 4044

– + bevacizumab

– 34 patients (18 EPT, 16 carcinoids)

– 12 prior chemo

– EPT 24% PR, carcinoids 0%

– PFS 8.6 months

Kulke; Clin Cancer Res 2009

– correlation MGMT-deficiency and response

Strosberg; Cancer 2011

– + capecitabine

– 30 patients with EPT

– first line

– PR 21/30 (70%)

Biotherapy in NET: Interferon

Studies

• Total of 27 studies, 679 patients

• Very few randomised controlled studies

• Biochemical and symptomatic responses,

but tumour remission is rare (~10%)

• Combination therapy with interferon +

somatostatin analogue was not superior to

somatostatin analogue monotherapy with

respect to tumour control1

• The incremental effect of interferon therapy

is low and it is poorly tolerated

1. Arnold R. et al Clin Gastroenterol Hepatol. 2005 Aug;3(8):761-71

Somatostatin Analogues for

Symptom Relief

• Somatostatin analogues, octreotide and lanreotide,

target somatostatin receptors (sstr), specifically subtype

2, to inhibit hypersecretion of hormones and bioactive

amines and peptides1; equally effective

– Approximately 80% of NETs express sstr22,3

– sstr2 is considered of particular therapeutic relevance

because of its abundance in GI and pNETs4

• sstr1–3 function to reduce tumour secretions and inhibit

tumour growth by promoting apoptosis and cell cycle

arrest5

1. Öberg K, Kvols L, Caplin M, et al. Ann Oncol. 2004;15:966-973 2. Mougey AM, et al. Hosp Phys. 2007:51:12-20. 3. Krenning EP, et al. Eur J

Nucl Med. 1993;20(8):716-731. 4. Hofland LJ, Lanberts SWJ. Endocr Rev. 2003;24:28-47 5. Florio T. Front Biosci. 2008;13:822-840.

42% REDUCTION in

Diarrhea Frequency1,2

4.3

2.5

0

1

2

3

4

5

Baseline Week 24

Med

ian

Nu

mb

er

of

Sto

ols

/Day

1. Rubin J, Ajani J, Schirmer W, et al. J Clin Oncol.1999;17:600-606. 2. Anthony L, Freda PU. Curr Med Res Opin. 2009;25:2989-2999.

4.5

0.7

0

1

2

3

4

5

Baseline Week 24

Med

ian

Nu

mb

er

of

Flu

sh

ing

s/D

ay

84% REDUCTION in

Flushing Frequency1,2

N = 47 N = 33

Octreotide LAR Provides

Effective Symptom Relief

Improvement Over Time in

Median Overall Survival

From an analysis of 35,825 cases of NETs

Yao JC et al. J Clin Oncol 2008;26:3063–3072

Survival in patients with NET and distant metastases was significantly longer 1988–2004 (post-octreotide) vs 1973–1987 (pre-octreotide)

Median Survival

1973-1987 18 months

1988-2004 39 months

Distant Metastases

Surv

ival

pro

bab

ility

Time (months)

1.0

0.8

0.6

0.4

0.2

0 12 24 36 48 60 72 84 96 108 120

Receptor Binding Affinities of Somatostatin,

Octreotide and Lanreotide

sst1 sst2 sst3 sst4 sst5

(1C50 nmol/L)

Somatostatin 0.93 0.15 0.56 1.50 0.29

Octreotide 280.000 0.38 7.10 >1000 6.30

Lanreotide >1000 0.80 107 >1000 5.20

Receptor Mediation of Cell Proliferation

sst1 sst2 sst3 sst4 sst5

Induction G1

cell cycle arrest

+ + + +

Induction of

apoptosis

+ +

Somatostatin Antiproliferative

Mechanism of Action

1. Susini C, Buscail L. Ann Oncol. 2006;17(12):1733-1742. 2. Mougey AM, Adler DG. Hosp Phys. 2007:51:12-20.

3. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Eur J Nucl Med. 1993;20(8):716-731. 4. Őberg KE et al. Gastroenterology 2010;139:742–753

• Somatostatin signaling inhibits secretory and proliferative activity1

• More than 80% of NET express somatostatin receptors2,3

AC = adenylyl cyclase; ER = endoplasmic reticulum; ERK = extracellular signal-regulated kinase; Gα, Gβ, Gγ, = G protein subunit; IP3 = inositol triphosphate; pHi = intracellular pH; PLC = phospholipase C; PTPase = phosphotyrosine phosphatase4

SRIF

Caspase 8 Wildtype p53 Bax pHI Endonuclease

G

G G

PLCβ/ IP3SHP-1

SHP-2 PTP-

PTPase

AC

Voltage

K+

K+

channelCa2+

channel

Ca2+

cAMP

Hormone

Secretion (frequently)

Apoptosis Cell growth

ERK1/2 ERK1/2 p27Kip1

Secretion (infrequently)

Ca2+

ER

Ca2+

channel

Summary of Non-randomized Clinical Trials Evaluating

the Antiproliferative Effect of Somatostatin Analogs

Analog Author n CR/PR SD PD

Patients with documented tumour progression

Lanreotide Faiss et al 2003 22 1(4) 7(32) 14(64)

Lanreotide Aparicio et al 2001 35 1(3) 20(57) 14(40)

Octreotide Arnold et al 1993 52 0(0) 19(36) 33(63)

Octreotide Saltz et al 1993 34 0(0) 17(50) 17(50)

Octreotide di Barholomeo et al 1996 58 2(3) 27(46) 29(50)

201 4(1) 90(45) 107(53)

Patients without documented tumour progression

Lanreotide Wymenga t al 1999 31 2(6) 25(80) 4(13)

Lanreotide Ducreaux et al 2000 39 2(5) 21(54) 16(41)

Lanreotide Eriksson et al 1997 19 1(5) 12(63) 6(32)

Lanreotide Tomasetti et al 1998 18 0(0) 14(77) 4(22)

Octreotide Tomasetti et al 1998 16 0(0) 14(87) 2(12)

Octreotide Ricci et al 15 1(6) 6(40) 8(53)

138 6(4) 92(67) 40(29)

Slow Release Formulations

Lanreotide-PR 30 mg i.m./10-14 days

Sandostatin-LAR 10, 20, 30 mg i.m./4 weeks

Lanreotide Autogel 60, 90, 120 mg s.c./4

weeks

Antiproliferative Effect of Lanreotide in Patients

with Progressive Disease; More Recent Studies

Study N= SSA Dose SD % PR

Panzuto et al 2006 35 OCT/

LAN

30 mg/28 days

60 mg/28 days 45 -

Bajetta et al 2004

30

30

LANMP

LANATG

60 mg/28 days

120 mg/42 days

64

68

4

Bianchi* et al 2011 23 LANATG 120 mg/28 days 65.3 9

Massuti et al 2011 30 LANATG 120 mg/28 days 88.9 3.7

Khan et al 2011 69 LAN - 54 -

*) Liver tumor burden <25% >50%

Stabilization at 12 mo 71% 17%

ATG: Autogel (60, 90 or 120 mg); MP: Micro particle (30 or 60 mg)

Binding of the

somatostatin receptor

on tumor cells

DIRECT

ANTIPROLIFERATIVE

EFFECT

INDIRECT

ANTIPROLIFERATIVE

EFFECT

Antiproliferative Effect of

Somatostatin Analogs

Inhibition of

cell cycle

Inhibition of

growth factor

effects

Pro-apoptotic

effect

Inhibition of the

release of growth

factor and

trophic hormones

Inhibition of cell

angiogenesis

Modulation of

immune system

Octreotide LAR

30 mg im / 28 days

Placebo

im / 28 days

RANDOMI S E

PROMID

Patients: • Well differentiated

midgut NETs

• Treatment-naïve

• Locally inoperable or metastasized

N = 85

Primary endpoint: • Median time to tumour progression

Rinke A, Barth P, Wied M, et al. J Clin Oncol. 2009;27:4656-4663.

1:1

Secondary endpoints: • Objective tumour response rate • Symptom control • Overall survival

Treatment until CT/MRI documented

tumour progression

or death

Phase III randomised, double-blind, placebo controlled study

Patient Characteristics

Octreotide LAR (n=42)

Placebo (n=43)

Total (n=85)

Median age, years (range) 63.5 (38–79) 61.0 (39–82) 62.0 (38–82)

Sex male (%) female (%)

47.6 52.4

53.5 46.5

50.6 49.4

Time since diagnosis, months (range) 7.5 (0.8–271.2) 3.3 (0.8–109.4) 4.3 (0.8–271.2)

Karnofsky score ≤80 (%) >80 (%)

16.7 83.3

11.6 88.4

14.1 85.9

Carcinoid syndrome* (%) 40.5 37.2 38.8

Resection of primary (%) 69.1 62.8 65.9

Hepatic tumour load 0% 0–10% 10–25% 25–50% 50%

16.7 59.5 7.1

11.9 4.8

11.6 62.8 4.7 9.3

11.6

14.1 61.2 5.9

10.6 8.2

Octreoscan positive (%) 76.2 72.1 74.1

Ki-67 up to 2% (%) 97.6 93.0 95.3

CgA elevated (%) 61.9 69.8 65.9

* Not requiring octreotide for symptom control

Rinke et al J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24

Octreotide LAR 30 mg Significantly

Prolongs Time to Tumour Progression

Octreotide LAR 30 mg: 42 patients / 26 events

Median TTP = 14.3 months [95% CI: 11.0–28.8]

Placebo: 43 patients / 40 events

Median TTP = 6.0 months [95% CI: 3.7–9.4]

Time (months)

Pro

po

rtio

n w

ith

ou

t p

rogr

essi

on

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78

Based on the conservative ITT analysis

66% reduction in the risk of tumour progression HR=0.34; 95% CI: 0.20–0.59; P=0.000072

Rinke et al J Clin Oncol. 2009 Oct 1;27(28):4656-63

Octreotide LAR 30 mg Improves TTP

Across Subgroups

Oct LAR = octreotide LAR 30 mg

Rinke A, Müller HH, Schade-Brittenger C, et al. J Clin Oncol. 2009;27:4656-4663.

Hazard Ratio and 95% Confidence Interval for Time to Tumour Progression

or Tumour-Related Death

Carcinoid syndrome (n=33) Inactive tumour (n=52) Liver involvement 0% (n=12) Liver involvement 0% - 10% (n=52) Liver involvement 10% - 50% (n=14) Liver involvement >50% (n=7) Chromogranin A elevated (n=56 Chromogranin A not elevated (n=27) Karnofsky Index >80% (n=73) Karnofsky Index <80% (n=12) Age <63 years (n=43) Age >63 years (n=42) Primary tumour resected (n=56) Primary tumour not resected (n=29)

Time to tumour progression (per protocol analysis)

Oct LAR Placebo Median (mo) Median (mo)

1 0.1 0.01 1.1

Favors placebo Favors octreotide LAR

14.3

5.5

28.8

5.9

13.1 29.4 11.2 4.6

8.2 6.1 5.5 2.8

14.3 28.8

5.6 8.5

27.1 11.5

28.8 14.3

5.8 6.1

8.3 5.7

29.4 10.3

5.9 5.6

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

HR=0.25 [95% CI: 0.10–0.59]

P=0.0008

Pro

po

rtio

n w

ith

ou

t p

rogr

essi

on

HR=0.23 [95% CI: 0.09–0.57]

P=0.0007

Pro

po

rtio

n w

ith

ou

t p

rogr

essi

on

Patients without carcinoid syndrome Patients with carcinoid syndrome

Time (months) Time (months)

Octreotide LAR: 17 pts / 11 events Median TTP 14.26 months

Placebo: 16 pts / 14 events Median TTP 5.45 months

Octreotide LAR: 25 pts / 9 events Median TTP 28.8 months

Placebo: 27 pts / 24 events Median TTP 5.91 months

Arnold R. Abst # 4508 presented at ASCO 2009, Orlando FL Rinke et al J Clin Oncol. 2009 Oct 1;27(28):4656-63

Octreotide LAR 30 mg Extends TTP in

Functioning and Non-functioning Patients

Predictors of Antiproliverative

Efficacy of Somatostatin analogs

Low hepatic tumor load and resection of primary

in midgut NETs (PROMID data)

Retrospective Data

Non-pancreatic primary

The absence of distant extra-hepatic

metastases

Ki-67 <5%

Liver involvement <25%

Stable disease before commencement of

treatment

Panzuto et al. Ann Oncol, 2006

Rinke et al. J Clin Oncol, 2009

Palazzo et al. ENETS, 2011 (abstract)

The CLARINET Study – Controlled Study of Lanreotide

Antiproliferation Response) in NET

Double-blind, placebo-controlled trial in non-functioning

GEP-NETs

204 patients were allocated to either Lanreotide Autogel,

120 mg q 28 days or placebo

Primary endpoint: The time to disease progression

(according to RECIST criteria) or death within 96 weeks

after first injection.

Primary tumour location: Pancreas (43.5%), Small

intestine (33.3%)

No previous tumour therapy 84%

Stable disease at inclusion 95%

44 centres in 14 countries

Final results in January 2014

Rationale for Combining

Everolimus and Octreotide LAR

• mTOR is a central regulator of

growth, proliferation,

metabolism, and angiogenesis1-

3

• NET have been linked to

genetic alterations that activate

the mTOR pathway2,3

• Everolimus inhibits mTOR3

• Octreotide downregulates IGF-

1, an upstream activator of the

PI3K/AKT/mTOR pathway4

• Everolimus + octreotide LAR

has shown activity in a phase II

trial5

1. O’Reilly T, McSheehy PM. Transl Oncol. 2010;3(2):65-79. 2. Meric-Bernstam F, Gonzalez-Angulo AM. J Clin Oncol. 2009;27:2278-2287.

3. Faivre S, Kroemer G, Raymond E. Nat Rev Drug Disc. 2006;5:671-688. 4. Susini C, Buscail L. Ann Oncol. 2006;17:1733-1742.

5. Yao JC, Phan AT, Chang DZ, et al. J Clin Oncol. 2008;26:4311-4318.

Growth and proliferation

IGF-1R

IGF-1

mTOR inhibitor

IGF-1R

IGF-1 VEGF

VEGFR

mTOR

Angiogenesis

Survival

Metabolism

VHL

TSC1/2

PTEN

NF1

X X X X

signaling

Caspase 8 p53 Bax

secretion ligands

SHP1

sstr1-5 sst analog

NFcb

Ca2·

K+

Treatment until disease progression

Crossover allowed at time of PD

1:1

R A N D O M I S E

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

Multi-phasic CT or MRI performed every 12 weeks

Enrollment January 2007 March 2008

Phase III, Double-blind, Placebo-controlled Trial

Patients with advanced NET and a history of secretory symptoms (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

Yao J, Hainsworth J, Baudin E, et al. 2011 Gastrointestinal Cancer Symposium; San Francisco, CA. Abstract # 158.

Primary Endpoint: PFS Statistical boundary = 0.0246

Secondary Endpoints: OS, ORR, biomarkers, safety, PK

Baseline Characteristics

Everolimus + Oct LAR (n=207)

Placebo + Oct LAR (n=203)

Median age, years (range) 60 (22-83) 60 (27-81)

Male : Female (%) 45:55 58:42

WHO PS (%)

0 55 66

1 / 2* 39/ 6 29/ 5

Primary site (%)

Small intestine 51 53

Lung* 15 5

Colon 7 7

Pancreas 5 7

Liver 3 5

Prior somatostatin analogues 80 78

Prior systemic antitumour therapies 46 38

Chemotherapy* 35 26

Immunotherapy 13 9

Targeted therapy 7 8

Other 10 12

Yao J, Hainsworth J, Baudin E, et al. 2011 Gastrointestinal Cancer Symposium; San Francisco, CA. Abstract # 158.

One missing PS in placebo arm; Oct LAR = octreotide LAR *Statistically significant for imbalance P<0.05

PFS by Central Review*

Time (months)

* Independent adjudicated central review committee

• P value is obtained from the one-sided log-rank test

• Hazard ratio 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

Pe

rce

nta

ge e

ven

t-fr

ee

Kaplan-Meier median PFS Everolimus + Octreotide LAR: 16.4 months Placebo + Octreotide LAR: 11.3 months

Hazard ratio = 0.77; 95% CI [0.591.00] P value = 0.026

Total events = 223 Censoring times E + O (n/N = 103/216) P + O (n/N = 120/213)

Yao J, Hainsworth J, Baudin E, et al. 2011 Gastrointestinal Cancer Symposium; San Francisco, CA. Abstract # 158.

123 placebo + octreotide LAR patients crossed over at

the time of progression

Adverse Events

• Grade 3/4 AEs (≥5%) included stomatitis

(7%), fatigue (7%), diarrhea (6%), infections

(5%), hyperglycemia (5%), and

thrombocytopenia (5%)

• Pulmonary events - all grades, 12%; grade

3/4, 2% - included pneumonitis, interstitial lung

disease, lung infiltration, or pulmonary fibrosis

Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.

[177Lu-DOTA0, Tyr3] Octreotate

310 patients

Dose 600-800 m Ci (22.2 to 29.6 GBq)

PR 30%

MR 16%

SD 35%

PD 20%

higher remission rates –

higher uptake on Octreoscan grade 3-4

Performance status KPS >70

Median time to progression: 40 mo

Serious adverse events:

MDS (3 patients), acute leukemia, liver toxicity (2 patients)

higher response rates but shorter duration in EPT

Kwekkeboom et al, JCO, 2008

Rationale for the Use of

Angiogenesis Inhibitors in NET

• NET are highly

vascularized and

express VEGF and

VEGF-R1

• VEGF expression

correlates with

decreased PFS

duration2

• Angiogenesis inhibitors

that target VEGF have

been shown to have

clinical activity in NET3

IGF-1

HER2

EGF

Metabolism

TSC1/2

PTEN

Aberrantly activated

PI3K/AKT/mTOR

pathway

Tumor Cell

Growth and proliferation

IGF-1R

mTOR ERK

RAF

MEK

EGFR

PDGFR

PDGF

Angiogenesis

Endothelial Cell

VEGF

VEGFR

Survival

Angiogenic factors

1.Yao JC, Phan AT, Hoff PM, et al. J Clin Oncol. 2008;26(8)1316-1323. 2. Phan AT, Wang L, Xie K, et al. J Clin Oncol. 2006;24(18s suppl):abstract

4091. 3. Eriksson B. Curr Opin Oncol. 2010;22(4):381-386.

Angiogenesis

Sunitinib vs Placebo in Advanced pNET

• Phase III randomised, placebo-controlled, double-blind trial

• Trial terminated after unplanned early analysis

Primary Endpoint:

• PFS

Statistical significance required

nominal critical z value ≥3.8809

Sunitinib 37.5 mg/day orally

Continuous daily dosing*

n = 86

Placebo*

n = 85

* With best supportive care

Somatostatin analogues were permitted

Raymond E, et al. N Engl J Med. 2011;364:501-513.

Secondary Endpoints:

• OS

• ORR

• TTR

• Duration of response

• Safety

• Patient-reported outcomes

R A N D O M I S E

1:1

Well differentiated

advanced pNET patients

(N = 171 enrolled / 340

planned)

• Disease progression in past

12 mo

• Not amenable to curative

treatment

0.8

0.6

0.4

0.2

0

1.0

Pro

po

rtio

n o

f P

atie

nts

5 10 15 20 25 0

Sunitinib

39 19 4 0 0 86 Sunitinib

28 7 2 1 0 85 Placebo

Number at risk

Time (mo)

Placebo

Kaplan-Meier median PFS

Sunitinib: 11.4 mo

Placebo: 5.5 mo

HR = 0.42 (95% CI, 0.26–0.66)

P<0.001; nominal critical z value = 3.8506

Progression-Free Survival*

Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.

* Local review

Adverse Events

• Grade 3/4 AEs (≥ 5%) in the sunitinib arm

included neutropenia (12%), hypertension

(10%), leukopenia (6%), PPE* (6%), asthenia

(5%), diarrhea (5%), fatigue (5%), and

abdominal pain (5%)

• Most frequently reported all-grade AEs with

sunitinib were diarrhea (59%), nausea (45%),

asthenia (34%), vomiting (34%), and fatigue

(33%)

Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.

* Palmar-plantar erythro-dysesthesia

Everolimus 10 mg/d + best supportive care*

n = 207

RADIANT-3: Study Design

Placebo + best supportive care1

n = 203

Multi-phasic CT or MRI performed every 12 weeks

Treatment until disease progression

Crossover allowed at time of PD

1:1

* Concurrent somatostatin analogues allowed

Randomization August 2007 - May 2009

Phase III Double-blind, Placebo-controlled Trial

Primary Endpoint: PFS Statistical boundary ≤0.025

Yao J, Shah M, Ito T, et al. NEJM 2011; 364:514-23.

R A N D O M I S E

Secondary Endpoints: OS, ORR, biomarkers, safety, PK

Patients with progressive advanced pNET, N=410 • Advanced low- or

intermediate-grade pNET

• Radiologic progression ≤12 months

• Prior antitumour therapy allowed

• WHO PS ≤2

Stratified by: • WHO PS

• Prior chemotherapy

Progression Free Survival

• P value obtained from stratified 1-sided log-rank test • Hazard ratio is obtained from stratified unadjusted Cox model

Kaplan-Meier median PFS Everolimus: 11.0 mo Placebo: 4.6 mo

Hazard ratio = 0.35; 95% CI 0.27–0.45 P value: <0.0001

Time (mo)

100

80

% E

ven

t-fr

ee

Censoring times Everolimus (n/N = 109/207) Placebo (n/N = 165/203)

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

1. Yao J, Shah M, Ito T, et al. NEJM 2011; 364:514-23. 2. Yao JC, et al. 35th ESMO Congress 2010; Milan, Italy; Abstract LBA9.

148 placebo patients crossed over to everolimus at the

time of progression

Conclusion 1

• Somatostatin analogs are the mainstay of the

therapy for hormonal symptoms in NETs

• Somatostatin analogs appear to contribute to tumour stabilization in >50% of patients

• Delay in time to progression x2 in midgut NETs (one randomized study)

• Low hepatic tumour load; resected primary (midgut);low Ki-67; stable disease; midgut origin seem to respond best for anti-tumour effect

• A role in control of tumour growth in some gastric NETs

• Can ultrahigh-doses improve the anti-tumour effect?

• Which is the best combination treatment with somatostatin analogs for anti-tumour effect?

Conclusion 2

Requirements for improved

therapeutic outcome in NET

• Applied classification and grading, possibly refined (Rindi et al. 2012; Ki-67 >5%)

• Identification of serum markers for early diagnosis and follow-up; age at diagnosis

• Markers that serve as predictors of response (SST, MGMT, PTEN? TSC2, mTOR?)

• Individualize treatment; best sequence?

• Establishment of Centres of Excellence with multidisciplinary specialized clinical teams for NET