NEUROENDOCRINE TUMORS:

Mohamed Abdulla M.D.Prof. of Clinical OncologyCairo University

Asyut Clinical Oncology Annual ConferenceNOVARTIS Symposium23/02/2016

“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.

20042003200220012000199919981997199619951994199319921991199019891988198719861985198419831982198119801979197819771976197519741973

0.00

1.00

2.00

3.00

4.00

5.00

6.00

0

100

200

300

400

500

600

Inci

denc

e pe

r 100

,000

- NE

Ts

Inci

denc

e pe

r 100

,000

– A

ll m

alig

nant

neo

plas

ms

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

Inci

denc

e Pe

r 100

,000

1.4019

73

Year

1975

1977

1979

1981

1983

1985

1987

1989

1991

1993

1995

1997

1999

2001

2003

NET Site

1.20

1.00

0.80

0.60

0.40

0.20

0

LungColonSmall intestineRectumPancreas

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

Colon NeuroendocrineStomach

29-year limited duration prevalence analyses based on SEER

Pancreas Esophagus Hepatobiliary0

100

1,100

NET Prevalence in the US, 20041,200

Median survival (1988 – 2004)103,312

cases (35/100,000)

No.

of c

ases

(th

ousa

nds)

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 months114 months39 months

NET: Demographics:

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

descending colon (<1%)

sigmoid colon (-12%)

Primary Tumor Localizations

est. % of all NENthymus bronchus esophagus stomach duodenum pancreas

jejunum/ileum cecum appendix

colonrectum

<115<1154

15

152

15

110

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 100120

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

EnterocyteEnterocyte

EnterocyteEnterocyte

Pathogenesis of Carcinoid:Proliferating

TumorHormones &

Peptides

SomatostatinReceptors

HormonalSyndromes

Rindi G, Wiedenmann B. Nat Rev Endocrinol. 2011;8(1):54-64

Pathogenesis of Carcinoid:

TRYPTOPHAN METABOLISM

NORMAL NET

1%

SEROTONIN

70%

SEROTONIN

FOREGUT MIDGUT HINDGUT

Aromatic L- Amino Acid Decarboxylase

Pathogenesis of Carcinoid:

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

Pathogenesis of Carcinoid:Somatostatin: The Natural Defense Mechanism:

SOMATOSTATIN

Somatostatin Receptors

Short Lived Bio-availability

Sustained Released – Longer Acting SOMOATOSTATIN ANALOGUE

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

Evolution of Terminology & Classification:Histopathologic Differentiation:

Wel

l D

iffer

entia

ted

Poor

ly

Diff

eren

tiate

d

Evolution of Terminology & Classification:AJCC Criteria of Grading:

Grade Mitotic Count (per

10 HPF)

Ki 67 Index (%)

G1 < 2 < 2G2 2 – 20 3 – 20G3 > 20 > 20

AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.

Evolution of Terminology & Classification: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

Cum

ulat

ive

Surv

ival

G1

G2

G3

G1 vs G2G1 vs G3G2 vs G3

P=0.040P<0.001P<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

Evolution of Terminology & Classification:Correlation of TNM Staging With Survival:

26 26La 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

Prop

ortio

n A

live

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

Evolution of Terminology & Classification: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 9Time (yr)

Primary tumour growth

Metastases

Flushing

Diarrhea

Death

Vague abdominal symptoms

Estimated time to diagnosis: 5 to 7 yr

*

*

*Symptoms of carcinoid syndrome

Evolution of Terminology & Classification: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 = 0.2595% CI: 0.13-0.51P = .00004

Median PFSEarly 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 = 0.2595% CI: 0.10-0.58P = .00062

CgA NSE Median PFSEarly 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 0Nonresp 38 26 12 5 1 1 0 0 0 Nonresp. 11 5 2 0 0 0 0

00

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 AtrophicGastritis

PPI H2RAs

Small cell lung cancer Prostate cancer Breast cancer Ovary Cancer

Chronic atrophic gastritis PancreatitisInflammatory bowel disease Irritable bowel syndrome Liver cirrhosisChronic hepatitis Colon cancer HCCPancreatic 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 arthritisSystemic inflammatory response syndrome Chronic bronchitisAirway obstruction in smokers

INFLAMMATORYDISEASES

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 NETsThree principles

• Control of hormonal symptoms

• Control of tumor growth

• Improvement of survival?

Symptomatictherapy

Surgicaltherapy

Antiproliferativetherapy

• Cure• Debulking• Treatment /

Prevention of complications

Resection of primary tumorin distant metastatic disease?

249 primary resected, MS = 7.4 yHellman 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 lifeBasu 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 SSTR2

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

al a

g ly

lyasns

cys ph e

ph e

ph e tr

p lyst

h r

ph e

t h r

s e r

cys

D-phe cy s

phe

ly sc

thyrs

Octreotide acetate

D-trp

Thr- ol

D-phe c

ly sv

alc y

y sS

tyr

s

Lanreotide

D-trp

Thr

- NH2

S

SomatostatinS

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

Placeboim/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

RANDOMIZE

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

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

Octreotide LAR vs placeboHR=0.34 P=0.000072[95% CI: 0.20–0.59]

Based on conservative ITT analysis

Prop

ortio

n W

ithou

t Pr

ogre

ssio

n

1.0

.75

.50

.25

00 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 84 900

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)

Prop

ortio

n W

ithou

t Pro

gres

sion

P=0.0007; HR=0.23 (95% CI: 0.09–0.57)

Prop

ortio

n W

ithou

t Pro

gres

sion

Patients with nonfunctioning tumours Patients with functioning tumours

Time (mo)Time (mo)

Octreotide LAR 30 mg: 17 pts/11 eventsMedian TTP 14.26 moPlacebo: 16 pts/14 eventsMedian TTP 5.45 mo

Octreotide LAR 30 mg: 25 pts/9 eventsMedian TTP 28.8 moPlacebo: 27 pts/24 eventsMedian 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):

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

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 StudyD

ESIG

NA

SSES

SMEN

TSA non-interventional cross sectional study to assess SYMptom

control in neuroendocrine tumors (NET)

Non-interventional, cross-sectional study273 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 MedicalhistoryTreatment 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 syndromeby Somatostatin analogs

Sym

ptom

atic

res

pons

e (%

)

0

25

50

75

100

Octreotide Octreotide LAR Lanreotide Lanreotide slow release / autogel

Mean: 74.2Median: 71

Mean: 77.3Median: 75

mean: 63.0median: 63

mean: 67.5median: 63

Modlin IM, et al. Alimentary Pharmacol Ther. 2010;31:169-88.

Studies (n) 11 7 1 7Patients (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 16DOX 81 21 6.5 12

Bukowski et al Carcinoids STZ + DOX + 5FU +cyclophosphamide

STZ + 5FU +

56

9

31

22

–

––

10.

8cyclophosphamide

Sun et al Carcinoids DOX + 5FU 25 15.9 4.5 15.7STZ + 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:

Streptozocin/5-Fu are RE-EMPOWERED in 2015: RR & Treatment Outcome:

Streptozocin/5-Fu are RE-EMPOWERED 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 SynthesisCell Growth Autophagy

Altered Metabolism

Increased Proliferation

Apoptosis Resistance

+++

+++

RTKAKT

PI3KRAS –RAF

MEK

Targeted Drugsin 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 = 203Multiphasic CT or MRI performed every 12 weeks

Treatment until disease progression

Patients with advancedpNET, N = 410

Stratified by:• WHO PS

• Prior chemotherapy

Crossover 1:1

RANDOMISE

Phase III, Double-Blind, Placebo-Controlled Trial

Primary Endpoint: PFSSecondary 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 : 42WHO PS (%) 0 / 1 / 2 67 / 30 / 3 66 / 32 / 3No. of disease sites(%) 1 25 31 2 41 32 ≥3 34 38Histologic Grade (%) Well differentiated 82 84 Moderately differentiated 17 15 Unknown 1 1Prior 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-3PFS by Investigator Review:

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

% E

vent

-free

0 2 46 8 10

No. of patients still at risk

Kaplan-Meier median PFSEverolimus: Placebo:

11.0 mo4.6 mo

Hazard ratio = 0.35; 95% CI 0.27–0.45P 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

020 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

RANDOMIZE

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)No. of patients still at riskE + OP + O

216213

202202

167155

129117

120106

102 84

8172

6965

6357

5650

5042

4235

3324

2218

1711

11 9

43

11

10

00

* 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 LARP + 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

Perc

enta

ge E

vent

-free

Kaplan-Meier median PFSEverolimus + octreotide LAR: 16.4 moPlacebo + octreotide LAR: 11.3 mo

HR = 0.77; 95% CI (0.59–1.00) P=0.026

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

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

Subgroup PFS Analysis:

*Independent adjudicated central reviewHR = everolimus + octreotide/placebo + octreotideUnstratified Cox model was used to obtain HR

E + O = everolimus + octreotide LARP + 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 + O0.77 16.4 11.30.78 12.0 8.6

0.78 19.2 13.00.75 13.9 11.0

0.85 13.7 13.00.73 17.1 11.1

0.67 21.8 13.90.81 13.6 8.3

0.74 18.3 13.00.82 13.7 7.5

0.77 18.6 14.00.72 13.6 5.60.39 29.9 13.00.77 14.2 11.0

0.81 14.3 11.10.63 25.2 13.6

0.70 13.9 8.70.78 19.2 12.0

Hazard Ratio

Favors E + O Favors P + O

0 10.4 0.8 1.4

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

Everolimus: Real World Trial:

Everolimus: Real World Trial:

Everolimus: Real World Trial:

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

RANDOMIZE

Placebo N = 97

Stratified by:• Prior SSA treatment (yes vs. no)• Tumor origin (stratum A vs. B)*• WHO PS (0 vs. 1)

Characteristic EverolimusN = 205

PlaceboN = 97

Age, median (range) 65 (22 – 86) 60 (24 – 83)Male / female 43% / 57% 55% / 45%

WHO performance status0 / 1 73% / 27% 75% / 25%

Race    Caucasian 79% 70%Asian 16% 19%Other* 5% 11%

Primary tumor siteLung 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 EverolimusN = 205

PlaceboN = 97

Tumor gradeGrade 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 0 097 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

Prob

abili

ty o

f Pro

gres

sion

-free

Sur

viva

l (%

)

Kaplan-Meier mediansEverolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43)

Censoring TimesEverolimus (n/N = 113/205)Placebo (n/N = 65/97)

Consistent Investigator-Assessed PFS

P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.

Everolimus vs PlaceboHR = 0.39 (95% CI, 0.28-0.54); P < 0.00001

205 171 148 132 108 93 75 59 33 15 5 097 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

Prob

abili

ty o

f Pro

gres

sion

-free

Sur

viva

l (%

)

No.of patients still at risk

Kaplan-Meier mediansEverolimus: 14.0 months (95% CI, 11.24-17.71) Placebo: 5.5 months (95% CI, 3.71-7.39)

Censoring TimesEverolimus (n/N = 98/205)Placebo (n/N = 70/97)

2 4 6 8 10 12 15 18 21 24 270 30

00

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 treatmentYes

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 10Everolimus 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 Survival Analysis

*P-value boundary for significance = 0.0002.P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.NS, not significant.

205 195 184 179 172 170 158 143 100 59 31 5 097 94 86 80 75 70 67 61 42 21 13 5 0Placebo

Everolimus

No. of patients still at risk

0 2 4 6 8 10 12 15 18 21 24 27 30Months

0

10

20

30

40

50

60

70

80

90

100

Prob

abili

ty o

f Ove

rall

Surv

ival

(%)

Censoring TimesEverolimus (n/N = 42/205)Placebo (n/N = 28/97)

Everolimus vs PlaceboHR = 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

% C

hang

e fr

om B

asel

ine

in S

ize

of T

arge

t Le

sion

s Everolimus Placebo

Increase in tumor size as best response Decrease in tumor size as best response100

75

50

25

0

25

50

75

100

************** *************

Best Overall Response EverolimusN = 205, n (%)

PlaceboN = 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 = 202Placebo

N = 98Drug-related adverse events All grades Grade 3/4 All grades Grade 3/4

Stomatitis* 63% 9% 19% 0Diarrhea 31% 7% 16% 2%Fatigue 31% 3% 24% 1%Infections† 29% 7% 4% 0Rash 27% 1% 8% 0Peripheral edema 26% 2% 4% 1%Nausea 17% 1% 10% 0Anemia 16% 4% 2% 1%Decreased appetite 16% 1% 6% 0Asthenia 16% 1% 5% 0Non-infectious pneumonitis‡ 16% 1% 1% 0Dysgeusia 15% 1% 4% 0Cough 13% 0 3% 0Pruritus 13% 1% 4% 0Pyrexia 11% 2% 5% 0Dyspnea 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)

EverolimusN = 202

PlaceboN = 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) 0Septic shock 1 (0.5) 0Lung infection 0 1 (1.0)Respiratory failure 1 (0.5) 0Dyspnea‡ 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: PFSSecondary 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 orallyContinuous daily dosing*

n = 86

Placebo*n = 85

*With best supportive careSomatostatin analogues were permitted

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

1:1

RANDOMIZE

89 89

0.8

0.6

0.4

0.2

0

1.0

Prop

ortio

n of

Pat

ient

s

5 10 15 20 250

Sunitinib

39 19 4 0 086Sunitinib28 7 2 1 085Placebo

Number at riskTime (mo)

Placebo

Kaplan-Meier median PFSSunitinib: 11.4 moPlacebo: 5.5 moHR = 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, years14

0.2

0.4

0.6

0.8

Ove

rall

Surv

ival

, pro

babi

lity

Imhof A, et al. J Clin Oncol. 2011;29(17):2416-1423.

No. of patients

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:

NEW COMERS:

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

NET – Treatment Algorithm:

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 loco- regional therapies