Dr. Christos Toumpanakis MD PhD FRCP

Consultant in Gastroenterology/Neuroendocrine Tumours

Hon. Senior Lecturer University College of London

Neuroendocrine Tumour Unit - ENETS Centre of Excellence

ROYAL FREE HOSPITAL, London,UK

Pancreatic Neuroendocrine Tumours

UCLH Cancer Collaborative

Pancreas Update Meeting

12th July 2017

Disclosures

NOVARTIS : advisory board, research grants, educational

grants

IPSEN : advisory board, research grants, educational

grants

PFIZER : advisory board, educational grants

Pancreatic Neuro-endocrine

Tumours

Sporadic

With MEN-1:

a. Parathyroid

adenomas

b. Pituitary

tumours

With other

genetic

syndromes

Von Hippel Lindau (VHL)

Neurofibromatosis (NF-1)

Tuberous sclerosis.

20-40% 60-80% Pancreas 100%

2-4 (Pancreatic polypeptide)

Non-

Functional

Rarely 95% Pancreas 90% <0.1 ACTH ACTHoma

15% 60-70% Pancreas 30%

Lung 50%

Jejunum 15%

<0.1 Growth hormone

GRFoma

45% 70% Pancreas 55%

Duodenum 45%

<0.1 Somatostatin Somatostatinoma

10% 50-80% Pancreas 0.01-0.1 Glucagon Glucagonoma

5% 40-70% Pancreas 90%

0.1 VIP VIPoma (Verner

Morrison)

5% 10% Pancreas 1-2 Insulin Insulinoma

25% 60-90% Duodenum 60% Pancreas 40%

1-1.5 Gastrin Zollinger-Ellison

Syndrome

Associated with MEN-1

Malignant %

Tumour Location

Incidence New cases/million population

Peptide Secreted

Name

Insulinoma Fasting hypoglycaemia,

low blood glucose,

and improvement

after administration

of glucose

(Whipple’s triad)

Gastrinoma • Recurrent/resistant

to treatment

peptic ulcers,

not related to

H.pylori & NSAIDs

• Chronic diarrhoea

responding to PPIs

VIPoma

Chronic diarrhoea,

hypokalaemia

and dehydration

Glucagonoma

New onset of DM,

weight loss

and

“migratory necrolytic erythema

Specific symptoms – Pancreatic NETs

Classification of NETS WHO 2010 classification

(a) well- differentiated neuroendocrine tumours of G1-grade (Ki67< 2%)

(b) well-differentiated neuroendocrine tumours of G2-grade (Ki67 2-20%)

(c) poorly differentiated neuroendocrine carcinomas with high grade (G3, Ki67>20%) malignant behaviour.

Diagnostic algorithm for p NETs

History – clinical

examination

• Chromogranin-A

• Fasting gut hormones

Triple phase CT c/a/p

FDG-PET scan

• High-grade tumours

• Suspected second

malignancy

• MRI liver

• MRI spine

• Tc-Bone scan

• EUS

Somatostatin Receptor Scintigraphy

(Octreoscan / Ga-68 PET)

Tissue diagnosis

Commencement of treatment

Clinical, biochemical & radiological follow-up

Treatment of p NETs

A) Medical control of

patient’s symptoms.

B) Resection of tumor

primary and if

possible, metastatic

lesions.

C) Control of tumor

growth in cases of

advanced disease.

D) Improvement and

maintenance of

patient’s quality of life.

Somatostatin Analogues

Lanreotide Autogel

Octreotide LAR

Somatostatin analogues in functional pancreatic NETs

VIPomas Glucagonomas GRFomas Insulinomas

Patients treated 31 32 9 55

Symptomatic

Improvement %

87 75 100 36

Biochemical

response %

87 78 100 45

4 weeks after first injection of

Somatostatin analogues

Wermers, Fatourechi et al, Medicine (Baltimore) 1996

Nikou, Toumpanakis et al, Hepatogastroenterology 2005

Vezzosi, Bennet et al, Eur J Endocrinol 2005

ENETS consensus guidelines for the management of NET.

Neuroendocrinology. 2012;95:71-176. NCCN guidelines: Neuroendocrine

tumors. V2.2013.

Control of tumour growth

for advanced p NET

Locoregional therapy

• Radiofrequency ablation (RFA)

• Embolization / chemoembolization /

radioembolization

MIBG, meta iodobenzylguanidine; mTOR, mammalian target of

rapamycin; PRRT, peptide-receptor radiotherapy; TKI, tyrosine kinase

inhibitor; VEGFR, vascular endothelial growth factor receptor.

Medical therapy

Nuclear medicine and Radiation

• Somatostatin analogues (SSAs)

• Interferon-α

• Molecular Targeted therapies

– mTOR inhibitors

– VEGFR inhibitors

– other TKIs

• Systemic Chemotherapy

• Tumor-targeted, radioactive therapy:

PRRT using e.g.

– 90Y-DOTATOC

– 177Lu –DOTATATE

• External Radiation (for bone, brain-

metastases)

• Brachytherapy (for liver metastases)

Primary endpoint: PFS (ITT, N=204)

P-value derived from stratified log-rank test; HR derived from Cox proportional hazard model.

HR, hazard ratio; ITT, intention-to-treat.

Lanreotide Autogel 120 mg

32 events / 101 patients

median, not reached

Placebo

60 events / 103 patients

median, 18.0 months [95% CI: 12.1, 24.0]

Lanreotide Autogel vs. placebo

p=0.0002 HR=0.47 [95% CI: 0.30, 0.73]

Pa

tie

nts

aliv

e a

nd

with

no

pro

gre

ssio

n (

%)

Time (months)

62%

22%

0 3 6 9 12 18 24 27 0

10

20

30

40

50

60

70

80

90

100

Progression-free survival and tumor growth with Lanreotide Autogel

in patients with enteropancreatic NETs:

Results from CLARINET, a randomized, double-blind, placebo-controlled study

Caplin et al, NEJM 2014

PFS: therapeutic effect in pre-defined subgroups

generally consistent with overall population

Caplin M, et al. New Engl J Med 2014

PFS in p NETs

Lanreotide : not reached

Placebo: 12.1 months

Streptozocin for pancreatic NETs

Author Date Regimen Number

Patients

Response % Survival

months

P value

Moertel 1980 STZ 42 36 16.4 NSD

5FU/STZ 42 63 26

Moertel 1992 CZT 33 30 18 P<0.03

5FU/STZ 34 45 17 P<0.004

DOX/STZ 38 69 26

Randomised Controlled trials (did not use RECIST criteria, nor did they report PFS)

Case Series

Author Date Regimen Number

Patients Response % Survival

months

Cheng 1999 STZ/DOX 16 6 -

McCollum 2004 STZ/DOX 16 6 20

Delaunoit 2004 DOX/STZ 45 36 24

Kouvaraki 2004 5FU/DOX/STZ 84 39 37

Turner 2010 5FU/CIS/STZ 49 38 32

Temozolomide for pNETs

Author Date Number

Patients

PNET Regimen Response

Rate (PNET)

Kulke 2006 29 11 TMZ/thalidomide 25 (45)

Chan 2012 34 15 TMZ/Bevacizumab 15 (33)

Ekeblad 2007 36 12 TMZ 14 (8)

Chan 2013 40 40 TMZ/Everolimus (40)

Strosberg 2011 30 30 TMZ/Capecitabine (70)

Welin 2011 25 10 (PDEC) TMZ/Capecitabine (+Bev 5pts) 33

Koumarianou 2012 15 7 mTMZ/Bevacizumab/LAR 64

Chemotherapy

to downstage NETs

1. Pancreatic NET + PV Tumour

2. STZ + 5FU+ ADR (5 cycles)

3. Surgery

1

2 3

Systemic Chemotherapy

1. Platinum-based chemotherapy is the

treatment of first choice in GEP-NECs with

good RR but short PFS.

2. A 55% cut-off level of Ki67 seems promising

predictive factor of response in NECs.

3. Streptozocin-based regimens induce

responses in 30-40% well-differentiated

pNETs.

4. Temozolomide combinations are promising

but direct comparison with streptozocin is

required.

5. More studies are needed to assess the

response in functional NETs.

6. Ki67 by itself cannot predict response in well-

diff NETs.

7. Chemotherapy seems to be the preferred

option in pNETs with rapid symptomatic and

radiological progression, however prospective

studies are needed.

Kouvaraki, M. A. et al. J Clin Oncol 2004

Toumpanakis et al, Best Pract Res Clin End Metab 2007

Sorbye et al: the NORDIC NEC study, Ann Oncol 2013

D.Metz & R.Jensen, Gastroenterology 2008

Sunitinib

Everolimus

Sunitinib Malate for the Treatment of

Pancreatic Neuroendocrine Tumors Eric Raymond, M.D et al, N ENGL J MED 2011; 364:501-513

• Double blind randomized study

• 171 patients

• Progression within 12 months

• Ki67 < 20%

• 69% had chemotherapy before

• Sunitinib 37.5mg vs placebo

PFS OR Deaths

Sunitinib 11.4

months

9.3% 9 (10%)

Placebo 5.5

months

0% 21 (25%)

Adverse effects :

30% : diarrhoea, nausea, vomiting, fatigue

10-20% : Hypertension, neutropenia

With the exception of diarrhea,

sunitinib had no impact on

global HRQoL

Vinik A et al, Target Oncol 2016

Five years after study closure, median OS was 38.6 (25.6-56.4) months for

sunitinib and 29.1 (16.4-36.8) months for placebo (P = 0.094), with 69% of

placebo patients having crossed over to sunitinib Faivre et al, Ann Oncol 2016

Learning point from Sunitinib trial

Oral Sunitinib can control tumour growth

in G1/G2

advanced & progressive pancreatic NETs

with potential favorable implications to OS

Everolimus for Advanced Pancreatic

Neuroendocrine Tumours (RADIANT-3)

James C. Yao et al, N ENGL J MED 2011; 364:514-523

• Double blind randomized trial

• 410 patients – 50% chemo-naive

• Ki67 < 20%

• Progression within 12 months

• Everolimus 10 mg vs placebo

PFS OR

Everolimus 11 months 5%

Placebo 4.6 months 2%

Adverse effects :

30% : aphthous ulcers,rash, diarrhoea, fatigue

10 – 30% : lower respiratory infections, interstitial pneumonitis

< 10% : cytopenias, hyperglycaemia

Everolimus prolonged PFS regardless of prior chemotherapy

Lombard-Bohas C et al, Pancreas 2015

Learning point from RADIANT-3 trial

Oral Everolimus can control tumour growth

in G1/G2

advanced & progressive pancreatic NETs

Peptide Receptor Radionuclide Therapy (PRRT)

The -emitter labelled somatostatin analogue delivers a lethal

radiation dose to the tumour cell.

Mechanism of Action

Tumour cell

Somatostatin

receptor

Tumour cell

Isotope + Sst

analogue

Computed tomography scans in a patient with a metastasized nonfunctioning endocrine pancreatic tumor before treatment (left) and 3 months after the last treatment (right)

Radiolabelled Somatostatin Analogue LU-177-DOTA,Tyr3

Octreotate in patients with endocrine

gastroenteropancreatic tumours Kwekkeboom et al JCO 2005;23:2754-2762

131 pts

CR 2%; PR 26%; MR 19%; SD 35%; PD 18%

Recent results of PRRT in p NETs

Isotope No Patients Stable

Disease

Partial

Response

Median

PFS

OS

Lu-177

DOTATATE

33 36% 54.5% 26 months 55 months

Lu-177

DOTATATE

68 25% 60% 34 months 53 months

Y-90

DOTATATE

29 - - 25 months 42 months

Ezziddin et al, Eur J Nucl Med Mol Imaging. 2014

Ezziddin et al, J Nucl Med, 2014

Rogowski et al, Future Oncol 2016

Salvage Treatment with Peptide Receptor Radionuclide Therapy

(PRRT) in patients with advanced VIPomas and severe Werner-

Morrison syndrome

2 patients with severe syndrome

and progressive disease, despite

previous SSTAs, chemotherapy

and molecular targeted treatment

had significant symptomatic,

radiological and metabolic

response post PRRT.

Yalchin et al, ENETS 2015

Neoadjuvant Treatment of Nonfunctioning Pancreatic

Neuroendocrine Tumors with [177Lu-DOTA0,Tyr3]Octreotate

29 pts included

9 had surgery post PRRT.

5 patients had a local recurrence

or developed liver metastases 8,

14, 22, 48, and 56 mo after

surgery.

Median PFS was 69 mo for

patients with successful surgery

(yellow line) and 49 mo for the

other patients (red line).

4 / 9 (44%) patients remained

disease-free with a median follow-

up of 59 mo (range, 7–96 mo)

after surgery.

Esther I. van Vliet et al. J Nucl Med 2015

Do combination treatments improve the

outcome of p NETs ?

Study Drugs Pts ORR

(%)

PFS

(m)

OS

(m)

COOPERATE-2 EVE

vs

EVE + PAS

160 6.2

20.3

16.8

16.4

> 34

> 34

CALGB 80701

EVE

vs

EVE + BEV

150 12

31

14.0

16.7

35.0

36.7

EVE : everolimus

PAS : pasireotide

BEV : bevacizumab

Kulke et al, ENETS 2015

Kulke et al, ASCO 2015

More adverse effects with

EVE + BEV

(hypertension 41 vs 12%

G3/G4 : 81 vs 49%)

Transarterial Hepatic Embolization and

Chemoembolization

Symptomatic benefit (40-80%)

Partial response : ~ 50%

? Survival benefit

Brown et al J Vasc Interv Radiol 1999;10(4):397-403

Chamberlain et al J Am Coll Surg 2000;190:432-445

Morbidity (fever, pain, hepatic failure, intestinal ischaemia)

Mortality

Careful selection of patients

Toumpanakis et al, Best Pract Res Clin End Metab 2007

New Clinical Trials with “cold” and “hot”

somatostatin analogues

• CLARINET FORTE

Administration of Lanreotide Autogel 120 mg every 2

weeks in patients with progressing p NETs, being on

Lanreotide 120 mg every 4 weeks

• REMINET

Lanreotide Autogel vs placebo in p NETs who responded to

chemotherapy or molecular targeted therapy

• COMPETE (PRRT vs everolimus)

In patients with p NETs who progressed despite “cold

somatostatin analogues or chemotherapy

New trials (2)

Name Design

SEQTOR

Phase III

(crossover

design)

Arm 1

Everolimus and then 5-FU + STZ

Arm 2

5-FU + STZ and then Everolimus

OCLURANDOM

Phase II

(progressive

despite SSAs,

Everolimus or

Chemotherapy)

Arm 1

Lu-177 DOTATATE

Arm 2

Oral Sunitinib

Which treatment and for Whom

Patient’s clinical status, co-morbidities and preferences

Tumour Histology

Positive uptake in Octreoscan or Ga-68 PET

Tumour burden

Tumour status

Predictive molecular markers ?

Cost??

G3 GEP-NETs Patient’s performance status 0-2

Systemic Chemotherapy

Ki67 > 55% Ki67 < 55%

Platinum-based

chemotherapy

Temozolomide-based

chemotherapy

Well differentiated

G3 GEP-NETs

? PRRT

? Molecular targeted

Disease progression

2nd Line Systemic Chemotherapy Sorbye at al, CANCER 2014

G1 & G2 pancreatic NETs

PS 3-4 SA or supportive care PS 0-2

Resectable disease

HPB Surgery

(primary +/- hepatic

metastases)

Non-resectable

Predominantly

Hepatic

Disease

TACE

RFA

G 1

asymptomatic

Somatostatin Analogues Systemic

chemotherapy

or

Everolimus /

Sunitinib

G 2

symptomatic or PD

PS : performance status

PD : progressive disease

PD

PD

PRRT

Treatment sequence in specific

,advanced (G1/G2) p NET, clinical scenarios

Non-functional p NETs

• High tumour volume, Ki67 > 10%

• Symptomatic

+/- radiological progression

Systemic chemotherapy

(everolimus / sunitinib)

Malignant insulinomas

Everolimus (Ki67<10%)

Systemic chemotherapy (Ki67> 10%)

PRRT

Advanced Gastrinomas

Systemic chemotherapy: limited efficacy

? PRRT

Advanced VIPomas / Glucagonomas

Very limited data Faivre et al, Cancer Met Rev 2014

Valle et al, Cancer Treat Rev 2014

Kulke et al NEJM 2009

Kwekkeboom et al JCO 2005

Kouvaraki M A et al. JCO 2004

NET

patient

Hepatobiliary

& GI

surgery

Radiology

&

Nuclear Medicine

Oncology

Pathology

Gastroenterology

Endocrinology

Cardiology

Genetics

Dieticians

Palliative care

&

Pain control

Specialist

NET

Nurses

Multi-Disciplinary Team (MDT)

approach for NETs

• Accurate diagnosis &

staging

• Evaluation of performance

status & quality of life

• Consensus agreement on

treatment plan

• Continuous reassessment,

discussion and peer

review of the individualized

treatment plan

Thank you