Advances in Diagnosis and Treatment of GI-NET by

Kjell Öberg, MD, PhD, Dept. of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden

Nashville Oct. 2011

The Overall Incidence of NETs Is Increasing

Rapidly Compared With All Malignant Neoplasms

2.00

0

1.00

3.00

4.00

5.00

6.00

0

100

200

300

400

500

600

5.25

Year 74 76 78 80 82 84 86 88 90 92 94 96 98 00 02 04

Incidence of all malignant neoplasms

Incidence of neuroendocrine tumors

Inc

ide

nce

of

NE

Ts

per

10

0,0

00

In

cid

en

ce

of a

ll ma

lign

an

t neo

pla

sm

s p

er 1

00

,00

0

• The incidence and prevalence of NETs has increased approximately

500% over the past 30 yr, which may be partially due to improved

diagnosis Source: US SEER database.

Adapted with permission from Yao JC, et al. J Clin Oncol. 2008:26:3063-3072.

Lawrence B, et al. Endocrinol Metab Clin North Am. 2011 Mar;40(1):1-18, vii.

NET Are More Prevalent Than Gastric

and Pancreatic Cancers Combined

Yao JC, et al. J Clin Oncol. 2008;26:3063-3072. 4

Column 1 = SEER data for 2005; all other columns = 29-year prevalence analyses based on SEER data for 2004.

Pre

vale

nce

Neoplasms

1,200,000

1,100,000

100,000

0

21,427 Cases

28,664 Cases

32,353 Cases

65,836 Cases

103,312 Cases

1,168,000 Cases

Areas with the most progress

• Tumor classification

• Biomarkers

• Molecular imaging

• Targeted therapy

WHO 1980 WHO 2000 WHO 2010

I. Carcinoid

1. Well-differentiated endocrine

tumor (WDET)*

2. Well-differentiated endocrine

carcinoma (WDEC)*

3. Poorly differentiated endocrine

carinoma/small-cell carcinoma

(PDEC)

1. NET G1 (carcinoid)

2. NET G2*

3. NEC G3

large-cell or small-cell type

II. Mucocarcinoid

III. Mixed forms carcinoid-

adenocarcinoma

4. Mixed exocrine-endocrine

carcinoma (MEEC)

4. Mixed adenoneuroendocrine

carcinoma (MANEC)

IV. Pseudotumor lesions 5. Tumor-like lesions (TLL) 5. Hyperplastic and preneoplastic

lesions

NET, neuroendocrine tumor–well differentiated; NEC, neuroendocrine carcinoma–poorly differentiated;

G, Grade

[Some numerals are purple. Are they to show which are as described in bullet point below?

• If the Ki67 index exceeds 20%, this NET may be labeled G3.

Neuroendocrine Neoplasms: NENs of the Gastroenteropancreatic (GEP) System

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

Grading of GEP-NENs According to ENETS

G1 G2 G3

Ki67 index <2 3–20 >20

(% of positive cells per 2000 counted cells*)

Mitotic count <2 2–20 >20

(10 HPF)

Correlation of WHO Classification and

Ki67 with Survival

Ekeblad et al Clin Cancer Res. 2008 Dec 1;14(23):7798-803.

P < 0.001

N=324

0.0

150

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n a

live

WHO I

WHO II

WHO III

100 50 0 250 200 350 300 months

P < 0.001

N=324

0.0

150

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n a

live

100 50 0 250 200 months

Ki67 ≥ 2

Ki67 < 2

ENETS TNM WORKING PROPOSAL

PANCREAS

Size increase

Proposal for TNM classification and disease staging for endocrine tumors of the pancreas

TNM

T-primary tumor

TX

T0

T1

T2

T3

T4

Primary tumor cannot be assessed

No evidence of primary tumor

Tumor limited to the pancreas and size <2cm

Tumor limited to the pancreas and size 2-4cm

Tumor limited to the pancreas and size >4cm or invading duodenum or bile duct

Tumor invading other organs (stomach, spleen, colon and adrenal gland) or wall of

large vessels (celiac axis or superior mesinteric artery)

For any T add (m) for multiple tumors

N-regional lymph

nodes

NX

N0

N1

Regional lymph node cannot be assessed

No regional lymph node metastatsis

Regional lymph node metastasis

M-distant metastases

MX

M0

M1*

Distant metastasis cannot be assessed

No distant metastases

Distant metastasis

*M1 specific sites defined according to Sobin and Wittekind Virchows Arch (2006) 449:395-401

La Rosa et al. Human Pathol 2009, 40:30

Correlation of TNM Staging with

Survival

Stage I

P < 0.001

Pro

po

rtio

n A

live

Stage II

Stage III

Stage IV

I (n=44)

II (n=44)

III (n=34)

IV (n=33)

Months Patients with pNET

0.00

0.25

0.50

0.75

1.00

0 48 496 144 192 240

Correlation of Tumour Grade with Survival

Grading proposal for

NET*

Grade Mitotic count

(10 HPF)

Ki67 index

(%)

G1 < 2 ≤ 2

G2 2–20 3–20

G3 > 20 > 20

1, Rindi G, et al. Virchows Arch. 2006;449:395-401; 2. Rindi G, et al. Virchows Arch. 2007;451:757-762 ;3. Pape UF, et al. Cancer. 2008;113:256-265.

0 50 100 150 200 250

Survival Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

Cum

ula

tive S

urv

ival G1

G2

G3

G1 vs G2

G1 vs G3

G2 vs G3

P = 0.040

P < 0.001

P < 0.001

* ENETS and AJCC grading system

Poorly differentiated tumours are always grade 3

Grade 3 tumours are not always poorly differentiated

N=193

- Appendix no

- Pancreas no

For NETs (wd NETs/NECs):

- Stomach yes

- Duodenum yes

- Jejunum/ileum yes

- Colon/rectum yes

For NECs (pd NECs): no

Comparability of ENETS 2006/2007 With

UICC/AJCC 2009 TNM Classifications

ENETS TNM

AJCC/UICC TNM

T1

Confined to pancreas, <2 cm

Confined to pancreas, <2 cm

T2

Confined to pancreas, 2–4 cm

Confined to pancreas, >2 cm

T3

Confined to pancreas, >4 cm,

or invasion of duodenum

or bile duct

Peripancreatic spread, but without major

vascular invasion (Truncus coeliacus, A.

mesent. sup.)

T4

Invasion of adjacent organs or

major vessels

Major vascular invasion

Comparison of the Criteria for the T category in the ENETS

and 7th Edition- AJCC/UICC TNM Classifications of

Pancreatic Neuroendocrine Tumors

Biomarkers GI-NET Integrating

Biomarkers into Care

Histopathology, tumor biology

Circulating markers

Response evaluation

Circulating tumor cells

Biomarkers in NETs

Molecular imaging

Type of marker Marker

Cytosolic NSE, PGP 9.5

Related to secretory granules Chromogranins

Related to synaptic vesicles Synaptophysin, VMAT

Intermediate filaments NF, CK HMW

Adhesion molecules N-CAM

Proliferation Ki67 (MIB1)

Immunohistochemically Detected

Neuroendocrine Markers

Receptors (targets for

diagnosis and therapy)

Somatostatin receptors

Dopamine receptors

Interferon receptors

Growth factor receptors

CgA

sst1

sst2

sst3

sst4

sst5

CgA

sst1

sst2

sst3

sst4

sst5

Case 1 Case 2

Somatostatin Receptor Subtypes

Somatostatin Receptor Expression

in Endocrine Pancreatic Tumors

Sst1 Sst2 Sst3 Sst4 Sst5 Fjällskog et al 19/28 24/28 13/28 26/28 16/28 Kulaksiz et al 21/69 54/69 54/69 ND 53/69 Papotti et al 30/33 37/48 30/48 8/33 29/48 PCR PCR

O’Toole, et al. Eur J Endocrinol. 2006; 155: 849-57.

Somatostatin receptor subtype and dopamine

D2 receptor mRNA levels in GEP NETs

n = 35 GEP NETs (19 pancreatic and 16 intestinal) RT-PCR

Growth factors in

neuroendocrine tumors

Carcinoids tumors Endocrine pancreatic tumors

stroma tumor stroma tumor

PDGF ++ ++ ++ ++

PDGF-bR ++ - ++ -

PDGF-aR ++ ++ + ++

TGF-b1 (+) + - -

TGF-b2 ++ ++ + +

TGF-b3 + + + +

LTBP +++ (+) +++ -

TGF-bRII ++ - ++ -

b-FGF +++ ++ +++ ++

b-FGF R ++ - ++ -

TGF-a (+) +++ ++ (+)

EGF-R + ++ + +

IGF-1 + ++ + ++

VEGF + +++ + +++

FLt-1 + +++ + +++

Biomarkers in NET

CgA is the best available

biomarker for diagnosis of NET

Elevated CgA may correlate

with tumor progression

CgA is elevated 80%–100% of

the time in NET

NSE is also expressed in NET

Not used as commonly as CgA

Often elevated in poorly

differentiated tumors

Other biomarkers are available,

but few have achieved

widespread acceptance

New biomarkers in NET are

needed to provide better

diagnostic and prognostic

information 5-HIAA = 5-hydroxy-3-indoleacetic acid

5-HT = serotonin

GHRH = gonadotropin hormone release hormone

hCG = human chorionic gonadotropin

ANP/BNP = atrial natriuretic peptide and

brain/ventricular natriuretic peptide

NSE = neuron-specific enolase

PYY = peptide YY Vinik A, et al. Pancreas. 2009;38:876-889.

CgA

Somatostatin Histamine

Substance P Glucagon

5-HIAA

5-HT

Gastrin

Insulin

Somatostatin Histamine

Substance P Glucagon

5-HIAA

5-HT

Somatostatin Histamine

Substance P Glucagon

5-HIAA

5-HT

NSE

Adrenomedullin

Alkaline phosphatase

Bradykinin

Catecholamines

GHRH

hCG α/β

Natriuretic peptide: ANP/BNP

Neurokinin A Neuropeptide K/L

PYY

The Chromogranin Family

Chromogranin A (CgA)

Chromogranin B (CgB)

Secretogranin II (CgC)

Secretogranin III (1B1075)

Secretogranin IV (HISL-19)

Secretogranin V (7B2)

Secretogranin VI (NESP55)

Taupenot L et al. N Engl J Med. 2003;348(12):1134-49

Focus on Chromogranin A

10

1

100

1000

10,000

Carcinoid EPT MEN1 PHEO Normal

log

Cg

A (

nm

ol/

L)

p-CgA

log

Cg

B (

nm

ol/

I)

p-CgB 100

1

0.1 Carcinoid EPT MEN1 PHEO Normal

10

Chromogranin A and B Levels in NET Patients

Taupenot L, et al. N Engl J Med. 2003;348:1134-1149.

A1-15

77 114 208

Chromostatin

Chromasin I Chromasin II

WE14

248 322 338

Catestatin

GE25

Parstatin

Pancreastatins

Vasostatins

378 400

409

437

Chromogranin A–Related Peptides

S

Overview of Chromogranin A

The Chromogranin Family1

Chromogranin A (CgA)

Chromogranin B (CgB)

Secretogranin II (CgC)

Secretogranin III (1B1075)

Secretogranin IV (HISL-19)

Secretogranin V (7B2)

Secretogranin VI (NESP55)

1. Taupenot L et al. N Engl J Med. 2003;348(12):1134-49

2. Oberg K and Stridsberg M. Adv Exp Med Biol. 2000.482:329-37

3. Janson ET et al. Annals of Oncology. 1997.8:685-690

A1-15

77

S

114 208

Chromostatin

Chromasin I Chromasin II

WE14

248 322 338

Catestatin

GE25

Parstatin

Pancreastatins

Vasostatins

378 400 409

437

Chromogranin A Related Peptides1

Serum CgA as Indication of Tumour Presence2,3

> 5 liver met 5 < liver met Lymph node met

100

1,000

10,000

100,000

Cg

A (μ

g/

L)

Non-tumour associated increases

of CgA

• Decreased renal function

• Type A gastritis

• Drugs

• Deteriorated liver function

• Inflammatory bowel disease

• Stimulation of the sympathetic

nervous system?

Correlation of Baseline CgA Levels

With Survival

26 Neuroendocrinology 2009 by Korse et al.

N=39

P=0.02

<100 n = 6

100–1000 n = 16

>1000 n = 16

Chromogranin A μg/L

Cu

mu

lati

ve s

urv

ival

Survival time (mo)

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

Low CgA

≤5000 g/L

CgA Levels Have Prognostic Value

• Levels are indicative

of tumor burden1

– An increase from

baseline

signals disease

progression

– A decrease from

baseline

may indicate a response

to treatment2

• An independent

predictor of survival3,4

5-yr survival based on CgA level3,4

1. Ericksson B, et al. Digestion. 2000; 62(suppl 1):33-38; 2. Jenson EH, et al. Ann Surg Oncol. 2007;14:780-785;

3. Ardill JES, Ericksson B. Endocrine Rel Cancer. 2003; 10:459-462; 4. Tiensuu Janson EM, Öberg KE. Bailliér’s

Clin Gasteroenterol. 1996; 1094:589-601.

80

60

40

20

0 S

urv

iva

l %

High CgA

>5000 g/L

Correlation of Early CgA and NSE

Responses to Everolimus with PFS in pNET

An early CgA or NSE response was defined as normalization or ≥ 30% decrease at week 4

Yao JC et al. 2010 J Clin Oncol. 28(1):69-76

Time Since Study Start (Months)

PF

S (

%)

HR=0.25

95% CI: 0.13-0.51

p=0.00004

Median PFS (months)

Early response (n/N=16/33) = 13.3

No early response (n/N=26/38) = 7.5

24 0 6 3 12 9 18 15 21 24 0 6 3 12 9 18 15 21

HR=0.25

95% CI: 0.10-0.58

p=0.00062

CgA NSE

Time Since Study Start (Months)

Median PFS (months)

Early response (n/N=17/28) = 8.6

No early response (n/N=10/11) = 2.9

Censored observations

PF

S (

%)

0

20

40

60

80

100

0

20

40

60

80

100

Pts at Risk

0 33 26 29 12 19 3 5 2 0 38 12 26 1 5 0 1 0

Resp. Nonresp

Pts at Risk

0 28 16 23 6 9 1 3 0 0 11 2 5 0 0 0 0 0

Resp. Nonresp.

Early CgA and NSE responses may be a predictive of PFS benefit and need to

be validated in a phase III trial

Paraneoplatic Antigen Ma2 (PNMA-2)

Autoantibodies in Small Intestine NETs

Cui T, et al. PloS ONE. 2010;5:e16010,1-11

PNMA-2

Cui T, et al. PloS ONE. 2010;5:e16010,1-11

Specific markers for

decisions on treatment

Role of MGMT in Modulating

Temozolomide Sensitivity

TMZ O6-MeG

Futile DNA Mismatch Repair

+ Apoptosis

Tumor Cell Death (cytotoxicity)

Tumor Cell Survival

Ubiquitination +

Degradation

MGMT

• Absence of MGMT expression

appears to be key to realizing

benefit with Temozolomide

- MGMT deficiency was

observed in 19 of 37 (51%)

pancreatic neuroendocrine

tumors and 0 of 60 (0%) GI

NETs

- This correlates with treatment

response

Kulke et al. Clin Cancer Res 2009; 15: 338-45

O6-Methylguanine DNA Methyltransferase (MGMT*)

Expression† May Predict Response to

Temozolomide in GEP-NETs

Kulke MH, et al. Clin Cancer Res. 2009;15:338-345.

Response Response Median Median

N (RECIST) (CgA) PFS (mo) OS (mo)

MGMT 16 0/16 0/10 9.3 19.1

positive

MGMT 5 4/5‡ 4/5 19.2 NR

negative

* MGMT is a DNA repair enzyme believed to induce cancer cell resistance to

O6-alkylating agents like temozolomide.

† MGMT expression studied by IHC.

‡ P<0.05.

NR = not reached.

mTOR Signaling Pathways

SOS Grb

Metabolism Angiogenesis

Growth &

Proliferation

Nutrients and

metabolites

4EBP1

Rheb

Receptor tyrosine

kinase

p70S6K

PI3K

IRS-1 RAS P P

TSC1/2

AKT

eIF4E

Protein synthesis

Cyclin D, p27

Glut 1 VEGF, PDGF-β

P P

HIF-1α

Everolimus mTORC1

Tuberous Sclerosis 2 (TSC2) Protein Expression

and Correlation With Survival in PETs*

Reprinted with permission from Missiaglia E, et al. J Clin Oncol. 2010;28:245-255.

©2010 by American Society of Clinical Oncology

*Pancreatic endocrine tumors.

Phosphatase and Tensin Homolog (PTEN) Protein

Expression and Correlation With Survival in PETs

Reprinted with permission from Missiaglia E, et al. J Clin Oncol. 2010;28:245-255.

©2010 by American Society of Clinical Oncology

Molecular Imaging: Functional

Techniques

• Octreoscan (somatostatin receptor scintigraphy)

• MIBG-scintigraphy (metaiodobenzylguanidine)

• PET (positron emission tomography) (11C-5-HTP, 18F-DOPA, 68Ga-DOTA-octreotide, 99Tc EDDA-

HYNIC-TOC)

• 11C-5HTP (hydroxytryptophan)

• 11C-Dopamine

• 18F-Dopamine

• 68Ga-DOTA-octreotide

• 99Tc EDDA-HYNIC-octreotide

• [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4

(GLP-1)

Specific Isotopes for NETs

68Ga-DOTATOC

68Ga-DOTATATE

68Ga-DOTANOC

68Ga-labeled Octreotide

68Ga-DOTATOC

• 68Ga positron emitter

• Half-life 68 min

• Generator production

• Better spatial resolution with PET than

SPECT

• Examination 1 h after injection—

logistical benefits

NET—Small Intestine

Gabriel M, et al. J Nucl Med. 2007;48:508-518.

84 Patients with Various NETs

68Ga-DOTATOC PET

SRS (99Tc-HYNICTOC or 111In-DOTATOC)

PET SPECT CT

Sens 97% 52% 61%

Spec 92% 92% 71%

11C-5-HTP-PET of a patient with

elevated gastrin levels showing a

duodenal gastrinoma not detected

by other methods

PET/CT with 11C-5-HTP

Results

Tumors were imaged by

PET in 95% (36/38)

SRS in 84% (32/38)

CT in 79% (30/38)

More lesions were detected with PET than with SRS and CT in

58% and equal number in 34%

The primary tumors (PT) were imaged by

PET in 84% (16/19)

SRS in 58% (11/19)

CT in 47% (9/19)

Several previously undiagnosed lesions were detected with PET,

most in the range of 0.5-1.5 cm (therefore easily overlooked at

CT) Orlefors et al. JCEM, 2005

Copyright © American Society of Clinical Oncology

Koopmans, K. P. et al. J Clin Oncol; 26:1489-1495 2008

Fig 3. (A) Computed tomography (CT) scan, (B) somatostatin receptor scintigraphy (SRS), (C) 18F-dihydroxy-phenyl-alanine (18F-DOPA) positron emission tomography (PET), and

(D) 11C-5-hydroxy-tryptophan (11C-5-HTP) PET of a 54-year-old male patient with metastatic islet cell tumor

Whole body FDG-PET

Frontal projection

Transaxial

Sagittal

in a poorly differentiated neuroendocrine tumor

A, survival distribution among patients in the FDG-PET–negative (black, dashed) or FDG-PET–positive (black, solid) groups

Binderup T et al. Clin Cancer Res 2010;16:978-985

©2010 by American Association for Cancer Research

Levels of CTCs in NETs

Khan M S et al. Clin Cancer Res 2011;17:337-345

©2011 by American Association for Cancer Research

Therapeutic Options NETs

Surgery

– Curative (rarely), Ablative (very often)

Debulking

– Radiofrequency ablation (RFA)

– Embolization/chemoembolization/radioembolization

(Spherex®)

Medical therapy

– Chemotherapy

– Biological treatment:

• Somatostatin analogs

• α-interferon

• m-TOR inhibitors

• VEGF R inhibitors

• Other TKI’s

Irradiation

– External (bone, brain-mets)

– Tumor targeted, radioactive therapy (MIBG, Y90-DOTATOC,

Lu177 -DOTATATE)

Factors Influencing the Therapeutic

Decision

• Type of NET-tumor

• WHO-classification

• TNM stage and grade

• Extent of liver involvement

• Functioning vs. non-functioning tumor

• Patients performance status

• Availability of different therapeutic

modalities

NB! The treatment of most patients is a

combination of surgery, PRRT and medical

treatment

With courtesy from Ulrike Garske

Hindgut, 48 year old lady

With courtesy from Ulrike Garske

Effect of therapy over time

Feb 09 Apr 09 July 09 Aug 09 Jan 10

With courtesy from Ulrike Garske

177Lu-DOTA-octreotate therapy The Uppsala experience

Results: CR 1 (1%)

PR 57 (31%) 43%

MR 20 (11%)

SD 99 (54%)

PD 8 (4%)

32 patients who responded or had SD later progressed

• 229 patients 96 (midgut), 13 (lung), 17 (rectal), 44 (non-functioning

pNET), 9 (gastrinoma), 6 (glucagonoma), 7 (paraganglioma/

pheochromocytoma)

• No. treatments: 842

• Follow-up (n=185): Mean 13 mo (range 2–57 mo)

[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), liver toxicity (2 patients)

Kwekkeboom et al, JCO, 2008

Temozolomide, alkylates DNA-bases (guanin)

discovered in 1981

oral imidazotetrazine with activity in advanced

melanoma and primary brain tumors

temozolomide and dacarbazine share the active

intermediary MTIC

has a high oral bioavailability (100%) and extensive

tissue distribution, and rapid penetration through blood-

brain barrier, 10-30%, (shown by PET)

New Medical Therapies

Chemotherapy Temozolomide

200 mg/m2 for 5

days q 4 w

Combination Temozolomide + Capecitabine

200 mg/m2 + 1500/d for 5

days q 4 w

Temozolomide + Capecitabine + Bevacizumab

150-200 mg/m2 + 1500 mg/d + 10 mg/kg

Day 10-15 1-14 day 14 q 2 w

Chemotherapy: Temozolomide

Ekeblad; Clin Cancer Res 2007 – 36 patients (35 foregut, 12 EPT, 12 bronchial, 7 thymus)

– median 2.4 prior anti-tumor medical regimen

– RR 14% (40% in low O6 MGMT), TTP 7 m

Isacoff; ASCO 2006 Abs #14023

– + capecitabine

– 17 patients, failed prior chemotherapy, histology?

– 1 CR, 9 PR (59%), duration 9 months

Kulke; ASCO 2006 Abs # 4044

– + bevacizumab

– 34 patients, 18 EPT, 16 carcinoids

– 12 prior chemotherapy

– EPT; RR 24%. Carcinoids RR 0%

– PFS 8.6 m

Association of MGMT Status with Response to

Temozolomide-Based Therapy

Treatment Response According to MGMT Status

N Radiologic Response

(RECIST)

Median PFS

(mos)

Median OS

(mos)

MGMT+ 16 0/16 (0%) 9.25 14

MGMT- 5 4/5 (80%) 19 Not reached

Immunohistochemical MGMT Status According to Tumor Type

N MGMT Deficient MGMT Intact

Pancreatic Neuroendocrine 37 19 (51%) 17 (49%)

Carcinoid 60 0 60(100%)

Kulke et al. Clin Cancer Res 2009; 15: 338-45

Capecitabin plus Temozolomide in

Pancreatic Endocrine Tumors

N=33

Capecitabin 750 mg/m2 x 2 Daily 1-14

Temozolomide 200 mg/m2 x 1 10-14

PR 70% (RECIST)

PFS 18 mo

Adverse events (Grade 3/4) 12%

Strosberg et al. Cancer. 2010 Sep.

Temozolomide-Based Chemotherapy

in Progressing PDECs After First-Line

Chemotherapy

N=25 (GI-NETS)

Treatment Tem alone N=5

Tem + Cap N=13

Tem + Cap + bev N=7

Responses

CR n=1 (4%) (48 mo)

PR n=7 (29%) (median 19 mo)

SP n=9 (38%) (median 18 mo)

Median PFS 6 mo (95%) CI 4-14 mo)

Median OS 22 mo (95% CI 8-27 mo)

Toxicity 1 Grade 3 hematol.tox

(Grade 3-4) 1 Grade 3 liver tox

1 patient developed diabetes

Welin S et al. Cancer 2011

FDG PET/CT

January 4, 2006 May 25, 2006

Capecitabin + Temozolomide + Bevazicumab

September 9, 2009

Capdevila, Tabernero. AACR Aug

2011;213-21

Molecular-targeted Therapies

in Neuroendocrine Tumors

• Angiogenesis inhibitors:

VEGF-Receptor-Tyrosinkinase-Inhibitor PTK787/ZK,

Anti-VEGF (Bevacizumab), Endostatin, (Thalidomide) • Molecular-targeted therapies:

Imatinib, Gefitinib, Sorafenib, Pazopanib, Dalotuzumab,

Sunitinib, Everolimus

• Novel Somatostatin analogs: Pasireotide (SOM230),

chimeric molecules (e.g. Dopastatin)

• Others: Tryptophan Hydroxylase Inhibitors

NET and angiogenesis

Main Antiangiogenic Compounds in Clinical Development

for Advanced Neuroendocrine Tumors

Abbreviations: BV, bevacizumab; CHT, chemotherapy; NR, not reached; PFS, progression-free survival; STAT, signal transducers and activators of transcription; rH, recombinant human; m, months

Capdevila, Tabernero. AACR Aug

2011;213-21

(More than) Angiogenesis inhibitors

Inhibitor PDGFR VEGFR FGFR FLT3 EGFR

Sunitinib

Sorafenib

Pazopanib

AMG706

Dovitinib

Sunitinib vs Placebo in Advanced PNETS—

Phase III Study

Phase III randomized, placebo-controlled, double-blind trial

– Trial stopped early

Primary end point: PFS

Secondary end points: OS, ORR, TTR, duration of response, safety & patient-reported outcomes

Eligibility criteria

Well-differentiated malignant PNET

Disease progression in past 12 mo

Not amenable to curative treatment

Arm A

Sunitinib 37.5 mg/d orally

Continuous daily dosing*

R

A

N

D

O

M

I

Z

A

T

I

O

N

Arm B

Placebo*

1:1

* With best supportive care.

Somatostatin analogues were permitted.

171/340 patients enrolled:

86 in sunitinib arm

85 in placebo arm

Prior treatment Sunitinib Placebo

Somatostatin analogues 21 (24.4) 19 (22.4)

Prior systemic treatment, n (%)

Any

Streptozocin

Anthracyclines

Fluoropyrimidines

57 (66.3)

24 (27.9)

27 (31.4)

20 (23.3)

61 (71.8)

28 (32.9)

35 (41.2)

25 (29.4)

Raymond et al. N Engl J Med. 2011;364:6

0.8

0.6

0.4

0.2

0

1.0

Pro

po

rtio

n o

f p

ati

en

ts

5 10 15 20 25 0

Sunitinib: 11.4 mo

39 19 4 0 0 86 Sunitinib

28 7 2 1 0 85 Placebo

Number at risk Time (mo)

Placebo: 5.5 mo

Kaplan-Meier Analysis of Progression Free Survival

Median PFS

Sunitinib:11.4 mo (95% CI 7.4–19.8)

Placebo: 5.5 mo (95% CI: 3.6–7.4)

HR=0.418 (95% CI: 0.263–0.662)

P=0.0001

Progression-Free Survival

Niccoli P, et al. J Clin Oncol. 2010;28(suppl):15s; Abstract 4000.

Initial dose of 50 mg/d in phase II trials was reduced to 37.5 mg/d due to toxicity

RECIST-Defined Objective Tumor

Response

Sunitinib

(n=86)

Placebo

(n=85)

Best confirmed tumor response, n (%)

Complete response

Partial response

Stable disease/no response

Objective progression

Not evaluable

2 (2.3)

6 (7.0)

54 (62.8)

12 (14.0)

12 (14.0)

0

0

51 (60.0)

23 (27.1)

11 (12.9)

Objective response rate, % (95% CI)

Two-sided p-value for treatment difference

9.3 (3.2, 15.4)

0.0066

0

Median (range) duration of response, months 8.1 (1.0–15.0) –

Stable disease >6 months, n (%) 30 (34.9) 21 (24.7)

Tumor responses were assessed using RECIST 1.1

Objective response rate = patients with complete or partial tumor response

mTOR Signaling Pathways

SOS Grb

Metabolism Angiogenesis

Growth &

Proliferation

Nutrients &

Metabolites

4EBP1

Rheb

Receptor Tyrosine

Kinase

p70S6K

PI3K

IRS-1 RAS P P

TSC1/2

AKT

eIF4E

Protein Synthesis

Cyclin D, p27

Glut 1 VEGF, PDGF-β

P P

HIF-1α

Everolimus mTORC1

Rationale for Combining

Everolimus and Somatostatin analogs

•Everolimus inhibits mTOR

•Octreotide downregulates IGF-1,

an upstream activator of the

PI3K/AKT/mTOR pathway

•Everolimus + octreotide LAR has

shown activity in a phase II trial

•PFS superior in Stratum 2 of

RADIANT-1

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

mTO

R

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+

RADIANT-1: Study Design

Advanced pancreatic NET with RECIST progression following

cytotoxic chemotherapy

– Stratum 1: No octreotide LAR 60 days prior to enrollment; received

everolimus 10 mg/d

– Stratum 2: Octreotide LAR ≥3 months prior to enrollment; received

everolimus 10 mg/d + octreotide LAR (≤30 mg, q28d)

Stratum 1

115 patients SCREEN

Stratum 2

45 patients

Treatment continues until tumor progression

Primary end point

• RR stratum 1

Secondary end point

• RR stratum 2

• Response

duration

• Safety

• PFS

• Survival

• PK

Everolimus and

octreotide LAR

Everolimus

Multiphasic CT or MRI performed at baseline and every 3 mo

RADIANT-1 PFS by Central Review

Everolimus Everolimus + Octreotide LAR

8 4 6

N = 115

Median PFS = 9.7 mo

0

20

40

60

80

100

Pro

ba

bil

ity (

%)

26 0 2 10 12 14 16 18 20 22 24

Time (mo)

54 81 58 0 115 111 36 25 15 12 5 3 3 1

Patients at risk:

Yao JC, et al. J Clin Oncol. 2010;28:69-76.

24 8 4 6

N = 45

Median PFS = 16.7 mo

0

20

40

60

80

100

Pro

ba

bil

ity,

(%

)

0 2 10 12 14 16 18 20 22

Time (mo)

0 21 32 22 45 39 19 14 10 8 3 3 1

Patients at risk:

Glycemic Control in Insulinoma Treated

With Everolimus

Glucose control at study

entry

Glucose control during

everolimus

Tumor

response PFS

Patient 1

57/female

MDACC

Depot octreotide, diazoxide,

dexamethasone, and

continuous enteral feeding

Normalization of glucose;

discontinuation of diazoxide and

nocturnal feedings

Partial response

16 mo

Patient 2

40/female

MDACC

Depot octreotide, diazoxide,

and glucose tablets

Normalization of glucose;

discontinuation of diazoxide and

glucose tablets

Partial response

29 mo

Patient 3

22/female

DFCI

Intermittent symptomatic

hypoglycemia despite use of

depot octreotide and diazoxide

Normalization of glucose

and discontinuation of diazoxide

Stable disease

6+ mo

Patient 4

66/male

UCSF

Glucose control requiring

nocturnal dextrose infusion

Normalization of glucose

and discontinuation of nocturnal

dextrose infusions

Stable disease

6+ mo

Kulke MH, et al. N Engl J Med. 2009;360:195-197.

Inhibition of mTOR Reduces Insulin Gene

Transcription and DNA Synthesis

1. Leibiger et al. Mol Cell. 1998;1:933-938. 2. Kwon G, et al. J Biol Chem. 2006;281:3261-3267.

Insulin-producing cell Peripheral tissue

mTO

R

Glucose

Nutrient

PI3-K

PDK

IRS

Akt TSC 1/2

LKB1

AMPK

PTEN

RAD001

Insulin production

Insulin release

Growth

Insulin receptor

PI3-K

PDK

Akt

mTOR RAD001

Glucose

transport Nutrient

metabolism

Insulin receptor

RADIANT-3 Study Design Phase III, Double-Blind, Placebo-Controlled Trial

Everolimus 10 mg/d +

best supportive care*

n = 207

Placebo +

best supportive care*

n = 203

Multiphasic CT or MRI performed every 12 wk

Treatment

until disease

progression

Patients with

advanced PNET,

N = 410

Stratified by:

WHO PS

prior

chemotherapy

Crossover

1:1

*Concurrent somatostatin analogues allowed.

R

A

N

D

O

M

I

Z

E

Primary end point: • PFS (RECIST)

Secondary end points: • Response, OS, biomarkers, safety, and PK

Randomization August 2007–May 2009.

Yao JC, et al. N Engl J Med 2011;364

PFS by Investigator Review

• P value obtained from stratified 1-sided log-rank test

• Hazard ratio is obtained from stratified unadjusted Cox model

No. of patients still at risk Everolimus

Placebo

207

203

189

177

153

98

126

59

114

52

80

24

49

16

36

7

28

4

21

3

10

2

6

1

2

1

0

1

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

0

1

0

0

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

Yao JC, et al. 35th ESMO Congress 2010; Milan, Italy; Abstract LBA9.

Subgroups (N)

HR

Median PFS (mo)

E P

Investigator review (410) 0.35 11.0 4.6 Central review* (410) 0.34 11.4 5.4 Prior chemotherapy Yes (89) 0.34 11.0 3.0 No (221) 0.41 11.1 5.5 WHO Performance Status

0 (279) 0.39 13.8 5.4

1 or 2 (131) 0.30 8.3 3.0

Age group

<65 yr (299) 0.39 11.0 4.5

≥65 yr (111) 0.36 11.1 4.9

Gender

Male (227) 0.41 11.0 4.6 Female (183) 0.33 11.0 3.3 Race Caucasian (322) 0.41 10.8 4.6 Asian (74) 0.29 19.5 3.8 Region America (185) 0.36 11.0 4.6 Europe (156) 0.47 10.8 4.6 Asia (69) 0.29 19.5 2.9 Prior long-acting SSA Yes (203) 0.40 11.2 3.7 No (207) 0.36 10.8 4.9 Tumor grade Well-diff. (341) 0.41 10.9 4.6 Moderately diff.(65) 0.21 16.6 3.0

Subgroup PFS Analysis

*Independent adjudicated central review. Hazard Ratio

Favors Everolimus Favors Placebo

0 1 0.4 0.8

Yao JC, et al. 35th ESMO Congress 2010; Milan, Italy; Abstract LBA9.

Best % Change From Baseline—Waterfall Plots

Everolimus

n (%)

Placebo

n (%)

Decrease in best % change from baseline 123 (64.4) 39 (20.6)

Zero change in best % change from baseline 11 (5.8) 10 (5.3)

Increase in best % change from baseline 43 (22.5) 112 (59.3)

% change in target lesion available but contradicted by

overall lesion response = PD

14 (7.3) 28 (14.8)

Patients for whom the best % change in target lesions was not available and patients for whom the best %

change in target lesions was contradicted by overall lesion response = UNK were excluded from the analysis;

percentages above use n as denominator.

-100%

-75%

-50%

-25%

25% 0%

50%

75%

100%

Everolimus (n = 191)

Be

st

% c

ha

ng

e f

rom

ba

se

lin

e

(ta

rge

t le

sio

ns

)

Placebo (n = 189)

Yao JC, et al. 35th ESMO Congress 2010; Milan, Italy; Abstract LBA9.

Main Planned/Ongoing Clinical Trials with Targeted

Therapies in Advanced Pancreatic Neuroendocrine

Tumors

Capdevila, Tabernero. AACR Aug

2011;213-21

RADIANT-2 Study Design Phase III, Double-Blind, Placebo-Controlled Trial

Everolimus 10 mg/d +

octreotide LAR 30 mg/28 d

n = 216

Placebo +

octreotide LAR 30 mg/28 d

n = 213

Treatment

until disease

progression

R

A

N

D

O

M

I

Z

E

Patients with

advanced NET

and a history

of symptoms

attributed to

carcinoid

syndrome

(N=429)

1:1

Multiphasic CT or MRI performed every 12 wk

Crossover

Primary end point:

• PFS (RECIST)

Secondary end points:

• Tumor response, OS, biomarkers, safety, PK

Enrollment January 2007March 2008.

Pavel M, et al. 35th ESMO Congress 2010; Milan, Italy; Abstract LBA8.

PFS by Central Review*

Time (mo) No. of patients still at risk 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 the 1-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

% E

ven

t-fr

ee

Kaplan-Meier median PFS

Everolimus + octreotide LAR: 16.4 mo

Placebo + octreotide LAR: 11.3 mo

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)

Pavel M, et al. 35th ESMO Congress 2010; Milan, Italy; Abstract LBA8.

Occurring in >10%

Everolimus + octreotide LAR

(n = 215)

Placebo + octreotide LAR

(n = 211)

All grades (%) Grade 3/4 (%) All grades (%) Grade 3/4 (%)

Stomatitis* 62 7 14 0

Rash 37 1 12 0

Fatigue 31 7 23 3

Diarrhea 27 6 16 2

Nausea 20 1 16 1

Infections* 20 5 6 1

Dysgeusia 17 1 3 0

Anemia 15 1 5 0

Weight decreased 15 1 3 0

Thrombocytopenia 14 5 0 0

Decreased

appetite 14 0 6

0

Peripheral edema 13 0 3 0

Hyperglycemia 12 5 2 1

Dyspnea 12 2 1 0

Pulmonary events* 12 2 0 0

Vomiting 11 1 5 1

Pruritus 11 0 4 0

Asthenia 10 1 7 1 *Related toxicities grouped for calculations.

Pavel M, et al. 35th ESMO Congress 2010; Milan, Italy; Abstract LBA8.

Treatment-Related Adverse Events

Novel somatostatin analogue - SOM230

Novel cyclohexapeptide

Binding affinity of different somatostatin

analogs to the five somatostatin receptors

Compound sst1 sst2 sst3 sst4 sst5

Somatostatin

0.93±0.12 0.15±0.02 0.56±0.17 1.35±0.4 0.29±0.04

Octreotide

280±80 0.38±0.08 7.10±1.4 >1000 6.3±1

Lanreotide

180±20 0.54±0.08 140±9 230±40 17±5

SOM230

9.3±0.1 1.0±0.1 1.5±0.3 >100 0.16±0.01

Data are mean IC50 ±SEM values (nmol/l)

Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: SOM230: a novel somatostatin peptidomimetic with

broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol

2002; 146: 707–716.

PROMID Study Design

Month -1 0 3 6 9 12 15 18

Screening

Informed

consent

Randomization

1:1

Continuation of

treatment if no

progression

Octreotide LAR 30 mg i.m. every 4 weeks

Placebo i.m. every 4 weeks

Primary endpoint: time to tumor progression

• Treatment was continued until CT or MRI documented tumor

progression (WHO)

• Follow-up until death

• CT and/or MRI were evaluated by a blinded central reader

Octreotide LAR Significantly

Increases Time to Tumor Progression

Octreotide LAR vs placebo P=0.000072

HR= 0.34 [95% CI: 0.20–0.59]

Octreotide LAR: 42 patients / 26 events

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

Placebo: 43 patients / 40 events

Median 6.0 months [95% CI: 3.7–9.4]

Time (months)

Pro

po

rtio

n w

ith

ou

t p

rog

res

sio

n

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 Arnold R. ASCO GI 2009 Abs#121

Phase II study pasireotide (SOM230) in patients

with metastatic NETs refractory or resistant to

Octreotide LAR®

N=45

Dose 600-900 µg b.id.

Outcome Reduction of clinical symptoms (flushing or

diarrhea)

CR+PR N=12 (27%)

CR N=3 (7%) Mean dur. 44 days

PR N=9 (21%) Mean dur. 72 days

RECIST 13/23 SD (57%)

Adverse events Nausea 27%

Abdominal pain 20%

Weight loss 20%

Hyperglycemia 16%

Molecular Pathway of Octreotide

Anti-proliferative Effects

• sst2 and sst5 binding

down-regulates MAPK

• sst2 binding affects the

P13K/Akt/mTOR

pathway and SHP1

signalling

• Anti-proliferative effect

also mediated via

protein tyrosine

phosphatase

(PTPase) modulation

sst5

↑ Apoptosis ↓ Cell growth

PI3K

PDK1

Akt

GSK3β

p53

Zac1

mTOR

p70S6K

sst2

G protein

SHP1

NF-KB

JNK

sst2

G protein

G protein

SHP1

SHP2

Src

PTPŋ

MAPK

p27

Florio T et al. Front Biosci 2008;13:822–840; Grozinsky-Glasberg S et al. Neuroendocrinology 2008;87:168–181;

Theodoropoulou M et al. Cancer Res 2006;66:1576–1582; Susini C & Buscail L. Ann Oncol 2006;17:1733–1742

Direct Effects

PKG

cGMP

Interferon and somatostatin receptors

Patient UBL - Chromogranin A

0

20

40

60

80

100

120

140

160

1 3 5 7 9 11 13 15

Months

Cg

A µ

g/m

l

SOM 230 SOM230+α-IFN

Pasireotide + IFN-α

Metastatic NET

Surgery, RF, embolization, other

debulking

WHO1 (G1) Ki67 <2% WHO2 (G2)

Ki67 >2 <20%

WHO3 (G3) Ki67 >20%

1st line SMS Streptozotocin + 5-FU/Dox Cisplatin + etoposide alternative IFN-α, everolimus Everolimus, sunitinib Temozolomide + capecitabine sunitinib + bevacizumab 2nd line Combinations Temozolomide ± capecitabine SMS ± everolimus, IFN sunitinib PRRT PRRT

Treatment Algorithm NET (Based on

Classification)

NET Multidisciplinary Teams

Patient

Endo-

crinologist

Oncologist Surgeon

Nuclear

Medicine

Pathologist

Tumor

Board

Patient

support

group

Gastro-

enterologist

Improving Access to Specialized

Care Improves Patient Outcomes

• Multidisciplinary centers

are associated with

improved survival for

patients with NETs

• Median survival of

patients with metastatic

NETs treated at

―centers of excellence‖*

is ≥3 times higher than

median survival of

patients with NETs in

SEER database

1. Yao JC, et al. J Clin Oncol. 2008;26:3063-3072; 2. Öberg K. Oral presentations at ENETS, CCNETS,

and NANETS, 2008; 3. Strosberg J. Poster presented at ASCO GI 2008.

Median survival of patients1-3

*Centers of Excellence = Uppsala Center, Sweden; the Moffitt Cancer Center, Tampa, FL, USA.

Thank you!

Centre of Excellence Endocrine

Tumors, Uppsala University

http://www.endocrinetumors.org/

E n d o c r i n e T u m o r s C e n t r e o f E x c e l l e n c e

endocrinetumors.org