Pancreatic neuroendocrine tumours

Pancreatic Neuroendocrine Pancreatic Neuroendocrine TumorTumor

Dr. Chirag DesaiDr. Chirag Desai, , MD, DM (Oncology)MD, DM (Oncology)

Hemato-oncology Clinic, Hemato-oncology Clinic, VEDANTAVEDANTA, , AhmedabadAhmedabad

[email protected]

NETs arise from cells which produce and secrete hormonesNETs arise from cells which produce and secrete hormones Most NETs are slow growing and malignant, with metastatic Most NETs are slow growing and malignant, with metastatic

potentialpotential Common sites of origin are:Common sites of origin are:

GI tractGI tract

LungsLungs

Pancreas Pancreas

22

Introduction to NETsIntroduction to NETs

Definitions: Classification, Grade, Definitions: Classification, Grade, and Stage and Stage

Classification = origin, tumor characteristics, behavior Classification = origin, tumor characteristics, behavior Different NET classification systems (WHO, ENET, AJCC) take Different NET classification systems (WHO, ENET, AJCC) take

into consideration different tumor characteristicsinto consideration different tumor characteristics

Grade = inherent biological aggressivenessGrade = inherent biological aggressiveness11

For example: low-grade malignant, intermediate-grade malignant,For example: low-grade malignant, intermediate-grade malignant,high-grade malignanthigh-grade malignant

Prognostic; may be independent from tumor stagePrognostic; may be independent from tumor stage

Stage = extent of diseaseStage = extent of disease22

For example, organ confined, locally invasive, metastatic, etc.For example, organ confined, locally invasive, metastatic, etc. Prognostic; may be independent from tumour gradePrognostic; may be independent from tumour grade

3

1. Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-27 2. Rindi G, et al. Virchows Arch. 2007;451:757-762.

NETs have been traditionally NETs have been traditionally classified as foregut, midgut, classified as foregut, midgut, or hindgut, depending on site or hindgut, depending on site of originof origin

Replaced by new Replaced by new tumor-based classification tumor-based classification method developed by World method developed by World Health Organization (WHO)Health Organization (WHO)

44

ClassificationClassificationTraditional MethodTraditional Method

WHO classification defines NETs by degree of tumor differentiation, WHO classification defines NETs by degree of tumor differentiation, with specific clinicopathological featureswith specific clinicopathological features

The WHO classification system is based The WHO classification system is based on the following criteria:on the following criteria:

Biological behavior (malignancy)Biological behavior (malignancy) MetastasesMetastases Ki-67 indexKi-67 index AngioinvasionAngioinvasion Tumor sizeTumor size Histological differentiation Histological differentiation Hormonal syndromeHormonal syndrome

55

Classification Classification World Health Organization MethodWorld Health Organization Method

WHO Classification:WHO Classification:NET Grouped By Prognostic FactorsNET Grouped By Prognostic Factors

apancreatic NET

Prognosis of Patients With NET

Good Poor

6Strosberg JR, et al. GI Cancer Res. 2008;2:113-125.Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-27.Strosberg JR, et al. GI Cancer Res. 2008;2:113-125.Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-27.

77

WHO Classification for NETWHO Classification for NET

Ong SL, et al. Pancreatology. 2009;9:583-600.

NeuroendocrineTumours

Site of Origin•GI tract•Pancreas•Lungs•Thyroid•Pituitary•Others

Malignant Potential•Benign•Benign or low malignant potential (uncertain)•Low malignant potential•Highly malignant

Functional Activity•Functioning•Non-Functioning

The Pancreas Is the Most Common Primary Location The Pancreas Is the Most Common Primary Location of NET Breakdown in Middle East & Asia Pacific of NET Breakdown in Middle East & Asia Pacific

RegionRegion

Stomach 6%

Liver 4%

Bile duct and gallbladder 3%Omentum/abdominal lining 1%Rectum 1%Ovary 1%Lung 1%

Hwang T, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C48.

Potential Reasons for Increased Potential Reasons for Increased Incidence and Prevalence in NETIncidence and Prevalence in NET

• Exact reasons are unknown but may include:Exact reasons are unknown but may include:

– Potential underdiagnoses and underreporting in the pastPotential underdiagnoses and underreporting in the past

– Improved diagnostic techniquesImproved diagnostic techniques

– Increased awareness of NET in the communityIncreased awareness of NET in the community

9

Clinical presentation of GI NETs varies widelyClinical presentation of GI NETs varies widely Often discovered incidentallyOften discovered incidentally

Symptoms due to:Symptoms due to: Mechanical bulkMechanical bulk FibrosisFibrosis Secretion of various hormonesSecretion of various hormones

Serotonin is most common Serotonin is most common substance secreted from GI NETsubstance secreted from GI NET

Serotonin release can cause Serotonin release can cause carcinoid syndromecarcinoid syndrome

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GI NETsGI NETsClinical PresentationClinical Presentation

Serotonin-producing GI NET (ileum)

Symptoms of carcinoid syndrome include:Symptoms of carcinoid syndrome include:

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GI NETsGI NETsCarcinoid SyndromeCarcinoid Syndrome

Rapid heart beat

Hypotension

Diarrhea

Flushing

Heart disease

Wheezing

Carcinoid syndrome is associated with metastatic disease

pNETs are rare, slow-growing pNETs are rare, slow-growing neoplasmsneoplasms

Symptoms from excess hormone Symptoms from excess hormone production or mechanical problemsproduction or mechanical problems

6.4% of all NETs are found in 6.4% of all NETs are found in pancreaspancreas

Incidence rate of 0.4 cases per Incidence rate of 0.4 cases per 100,000 persons100,000 persons

Incidence is increasingIncidence is increasing

pNETs may or may not have pNETs may or may not have secretory symptomssecretory symptoms

Secretory symptoms related to Secretory symptoms related to specific hormonesspecific hormones

Tumors (nonfunctional) may secrete Tumors (nonfunctional) may secrete peptides but cause no clinical peptides but cause no clinical symptoms symptoms

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Pancreatic NETs OverviewPancreatic NETs Overview

Pancreatic NETs TypesPancreatic NETs Types

TumorIslet cell

typePredominant hormone

producedMalignant potential

Gastrinoma Gamma Gastrin Very high

Insulinoma Beta Insulin Low

Glucagonoma Alpha Glucagon Very high

VIPoma Delta Vasoactive intestinal peptide High

Somatostatinoma Delta Somatostatin Very high

PPoma PP cells Pancreatic polypeptide Very high

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Relative frequency: Asymptomatic >Insulinoma > Gastrinoma > Glucagonoma > VIPomas > Somatostatinoma > Others

Tumors without secretory symptoms are not associated with a Tumors without secretory symptoms are not associated with a hormonal syndromehormonal syndrome

Often found incidentallyOften found incidentally Patients present late with large malignancies or advanced diseasePatients present late with large malignancies or advanced disease

Symptoms due to tumor growth or spreadSymptoms due to tumor growth or spread Abdominal painAbdominal pain JaundiceJaundice DiarrheaDiarrhea IndigestionIndigestion Weight lossWeight loss

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Pancreatic NETsPancreatic NETsClinical Presentation—Asymptomatic pNETsClinical Presentation—Asymptomatic pNETs

Natural History of Neuroendocrine Natural History of Neuroendocrine TumoursTumours

15Vinik A, et al. Pancreas. 2009 Nov;38(8):876-89

11 22 33 44 55 66 77 88 99

Time, yearsTime, years

Primary tumour growthPrimary tumour growthPrimary tumour growthPrimary tumour growth

MetastasesMetastasesMetastasesMetastases

FlushingFlushingFlushingFlushing

DiarrheaDiarrheaDiarrheaDiarrhea

DeathDeathDeathDeath

Vague abdominal symptomsVague abdominal symptomsVague abdominal symptomsVague abdominal symptoms

Estimated time to diagnosis: 5 to 7 yearsEstimated time to diagnosis: 5 to 7 yearsEstimated time to diagnosis: 5 to 7 yearsEstimated time to diagnosis: 5 to 7 years

**

**

**Symptoms of carcinoid syndrome

Nonspecific Symptoms Are CommonNonspecific Symptoms Are Commonto Multiple Diagnosesto Multiple Diagnoses

Menopause

Irritable Bowel Syndrome

Functional Bowel Disease

Anxiety

Neurosis

Food Allergy

Asthma

Alcoholism

Thyrotoxicosis

Peptic Ulcer

NET

SymptomsSymptoms

• • Sweating • FlushingSweating • Flushing• • DiarrheaDiarrhea

• • Intermittent abdominal painIntermittent abdominal pain•• Hypoglycemia Hypoglycemia •• Confusion Confusion

• • BronchoconstrictionBronchoconstriction• • Dyspepsia •Dyspepsia • GI bleedingGI bleeding

• • Cardiac diseaseCardiac disease

16Aggarwal G, et al. Cleve Clin J Med. 2008;75(12):849-855.

Incidence of NET is increasing Incidence of NET is increasing More prevalent than other cancers (ie, stomach, pancreas, More prevalent than other cancers (ie, stomach, pancreas,

esophagus)esophagus)

Associations between these symptoms suggest the Associations between these symptoms suggest the presence of NET over more common ailmentspresence of NET over more common ailments

Flushing with NET is unrelated to time or day, warmth, or Flushing with NET is unrelated to time or day, warmth, or perspirationperspiration

Hormone production differs from menopause, which is a typical Hormone production differs from menopause, which is a typical misdiagnosismisdiagnosis

Elevated chromogranin A (CgA) is the generally accepted Elevated chromogranin A (CgA) is the generally accepted marker for NETmarker for NET

80% to 100% of NET, regardless of symptoms, secrete CgA80% to 100% of NET, regardless of symptoms, secrete CgA

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Importance of Raising the Index of Importance of Raising the Index of SuspicionSuspicion

Peracchi M, et al. Eur J Endocrinol. 2003;148(1):39-43.

History and physical examHistory and physical exam

Biochemical markers (serum, tissue, urine)Biochemical markers (serum, tissue, urine)11

SerumSerum TissueTissue Urinary Urinary

ImagingImaging22

Computed tomography scan (CT)/ Magnetic Computed tomography scan (CT)/ Magnetic Resonance Imaging (MRI)Resonance Imaging (MRI)

Nuclear Imaging Nuclear Imaging Endoscopic ultrasound (pNET only)Endoscopic ultrasound (pNET only)

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Systematic Approach to Systematic Approach to Diagnosing NET Is NeededDiagnosing NET Is Needed

1. Ferolla P, et al. J Endocrinol Invest. 2008;31(3):277-286.2. Barakat MT, et al. Endocr Rel Cancer. 2004;11(1):1-18.

Treatment Treatment

2020

Depending on the results obtained from a workup, a patient’s Depending on the results obtained from a workup, a patient’s NET is classified as local, regional, or advanced.NET is classified as local, regional, or advanced.

Treatment goals should be curative where possible, with the use Treatment goals should be curative where possible, with the use of pharmacological management as necessary.of pharmacological management as necessary.

General Treatment Goals:General Treatment Goals:

Local Regional NETLocal Regional NETThe treatment goal for localized NETs is curative, which The treatment goal for localized NETs is curative, which

is most often accomplished with surgery.is most often accomplished with surgery.

Advanced NETAdvanced NETThe treatment goal for metastatic tumors is also curative The treatment goal for metastatic tumors is also curative

surgery if possible, followed by pharmacological treatment.surgery if possible, followed by pharmacological treatment.

General NET Treatment GoalsGeneral NET Treatment Goals

Therapeutic Options for Advanced Therapeutic Options for Advanced Neuroendocrine Tumours (NETs)Neuroendocrine Tumours (NETs)

SurgerySurgery Curative (rarely), ablative (very often)Curative (rarely), ablative (very often)

DebulkingDebulking Radiofrequency ablation Radiofrequency ablation Embolization / chemoembolization / radioembolization (SpherexEmbolization / chemoembolization / radioembolization (Spherex®®))

Medical therapyMedical therapy ChemotherapyChemotherapy Biological targeted agentBiological targeted agent

Somatostatin analogs IFN-Somatostatin analogs IFN-αα Targeted molecular therapy Targeted molecular therapy

VEGF-R inhibitorsVEGF-R inhibitors

mTOR inhibitorsmTOR inhibitors

Other TKIsOther TKIs

IrradiationIrradiation External (bone, brain metastases)External (bone, brain metastases) Tumour-targeted, radioactive therapy Tumour-targeted, radioactive therapy ((9090Y- DOTATOC, Y- DOTATOC, 177177Lu- DOTATATE)Lu- DOTATATE)

Somatostatin analoguesSomatostatin analogues

Interferon-alfaInterferon-alfa

Chemotherapy Chemotherapy

Peptide receptor–targeted therapyPeptide receptor–targeted therapy

Molecular-targeted therapiesMolecular-targeted therapies

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Current Systemic Treatment Options for Current Systemic Treatment Options for Patients With Advanced NETs Patients With Advanced NETs

Several types:Several types: Somatostatin analoguesSomatostatin analogues

Currently approved for the relief of certain symptoms associated with symptomatic Currently approved for the relief of certain symptoms associated with symptomatic (functional) (functional) GI NETs and pNETsGI NETs and pNETs

Cytotoxic therapyCytotoxic therapyGI and Lung NETs: An option when no other options are feasible because of the poor GI and Lung NETs: An option when no other options are feasible because of the poor efficacy and toxicity. Single-agent and combination therapies with doxorubicin, 5-FU, efficacy and toxicity. Single-agent and combination therapies with doxorubicin, 5-FU, dacarbazine, actinomycin-D, cisplatin, alkylating agents, etoposide, streptozotocin, and dacarbazine, actinomycin-D, cisplatin, alkylating agents, etoposide, streptozotocin, and carboplatin have resulted in response rates from 20-50%.carboplatin have resulted in response rates from 20-50%.pNETs: Systemic chemotherapy is recommended for patients with unresectable liver or pNETs: Systemic chemotherapy is recommended for patients with unresectable liver or lung metastases. Trials using doxorubicin, streptozocin, 5-FU, temozolomide, and lung metastases. Trials using doxorubicin, streptozocin, 5-FU, temozolomide, and dacarbazine have established cytotoxic effects in pNETs.dacarbazine have established cytotoxic effects in pNETs.

Biological TreatmentBiological TreatmentInterferonInterferonHormone-like proteins normally made by white blood cells to help the immune system Hormone-like proteins normally made by white blood cells to help the immune system fight infectionsfight infectionsSometimes helpful in shrinking or slowing growth of advanced NETs and improving Sometimes helpful in shrinking or slowing growth of advanced NETs and improving symptoms of symptoms of carcinoid syndromecarcinoid syndrome

Pharmacological Treatment of NETPharmacological Treatment of NET

Several types:Several types:

Targeted TherapiesTargeted TherapiesDesigned to attack some specific aspect of cancer cellsDesigned to attack some specific aspect of cancer cellsA number of investigational therapies have shown preliminary A number of investigational therapies have shown preliminary evidence of activity in patients with advanced NETsevidence of activity in patients with advanced NETsTargeted Therapies:Targeted Therapies:

mTOR InhibitorsmTOR Inhibitorseverolimus (AFINITOR)everolimus (AFINITOR)

Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorssunitinib, sorafenibsunitinib, sorafenib

VEGF InhibitorsVEGF Inhibitorsbevacizumabbevacizumab

Other AgentsOther AgentsPasireotide, a multiligand somatstatin analogue, is currently in phase Pasireotide, a multiligand somatstatin analogue, is currently in phase III development for NETIII development for NET

Pharmacological Treatment of NET (Continued)Pharmacological Treatment of NET (Continued)

Somatostatin (SST) Somatostatin (SST) receptors are highly receptors are highly expressed on the expressed on the surface of GI NETssurface of GI NETs

More than 80% of all More than 80% of all NETs express SST NETs express SST receptorsreceptors

Overexpression Overexpression provides provides basis for regulation by basis for regulation by SSTSST

SST receptor activation SST receptor activation inhibits secretory and inhibits secretory and proliferative activityproliferative activity

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PathophysiologyPathophysiologySignificance of Somatostatin SignalingSignificance of Somatostatin Signaling

Octreotide May Have a Direct Octreotide May Have a Direct Antitumour Effect via sstAntitumour Effect via sst22 and sst and sst5 5

sst5

↑ Apoptosis ↓ Cell growth

PI3K

PDK1

Akt

GSK3β

p53

↑Zac1

mTOR

p70S6K

sst2

JNK

G protein

SHP1

NF-KB

sst2

G protein

G protein

SHP1

SHP2

Src

PTPŋ

MAPK

p27

cGMP↓

PKG↓

• sst2 and sst5 both downregulate MAPK

• sst2 binding effects the P13K/Akt/mTOR pathway and SHP1 signalling

• Antiproliferative effect also mediated via protein tyrosine phosphatase (PTPase) modulation

Florio T et al. Front Biosci 2008;13:822–840Grozinsky-Glasberg S et al. Neuroendocrinology 2008;87:168–181Theodoropoulou M et al. Cancer Res 2006;66:1576–1582

Alterations in the mTOR pathway result in the development of some Alterations in the mTOR pathway result in the development of some NETsNETs

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PathophysiologyPathophysiologySignificance of the mTOR PathwaySignificance of the mTOR Pathway

mTOR is a central regulator of mTOR is a central regulator of growth, proliferation, metabolism, growth, proliferation, metabolism, and angiogenesisand angiogenesis1-31-3

NET have been linked to genetic NET have been linked to genetic alterations that activate the alterations that activate the mTOR pathwaymTOR pathway2,32,3

Everolimus inhibits mTOREverolimus inhibits mTOR33

Octreotide downregulates IGF-1, Octreotide downregulates IGF-1, an upstream activator of the an upstream activator of the PI3K/AKT/mTOR pathwayPI3K/AKT/mTOR pathway44

Everolimus + octreotide LAR has Everolimus + octreotide LAR has shown activity in a phase II trialshown activity in a phase II trial55

Rationale for Combining Everolimus and Rationale for Combining Everolimus and Octreotide LAROctreotide LAR

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 andproliferation

PI3K

IGF-1RIGF-1RIGF-1RIGF-1R

IGF-1IGF-1IGF-1IGF-1

mTORinhibitor

IGF-1RIGF-1RIGF-1RIGF-1R

IGF-1IGF-1IGF-1IGF-1

VEGFVEGFVEGFVEGF

VEGFRVEGFRVEGFRVEGFR

mTOR

Angiogenesis

Survival

Metabolism

HIF1

a

VHL

TSC1/2

PTEN

NF1

AKT

XX XX XXXX

signaling

Caspase 8p53Bax

Caspase 8p53Bax

secretionligands

SHP1

MAPK

cGMP

sstr1-5sstr1-5sstr1-5sstr1-5

cAMP

sst analogsst analogsst analogsst analog

NFcbNFcb

CaCa2·2·

KK++KK++

Phase III randomized, double-blind, placebo-controlled studyPhase III randomized, double-blind, placebo-controlled study

Primary endpoint: Time to tumour progression (blinded central review)Primary endpoint: Time to tumour progression (blinded central review)

Secondary endpoints: objective response rate, survival, quality of life, safetySecondary endpoints: objective response rate, survival, quality of life, safety

PROMID: Evaluation of the PROMID: Evaluation of the Antiproliferative Effect of Octreotide LAR Antiproliferative Effect of Octreotide LAR

30 mg30 mg

Patients with midgut NETs

• Treatment naïve• Histologically confirmed • Locally inoperable

or metastatic• Well differentiated• Measurable (CT/MRI)• Functioning or non-

functioning

Octreotide LAR 30 mg im

every 28 days

Placebo im every 28 days

RA

ND

OM

IZA

TIO

N (

1:1)

Treatment until CT/MRI documented

tumour progression

or death

Month 3 6 9 12 15 18

Rinke A et al. J Clin Oncol 2009;27:4656–4663

Patient DemographicsPatient DemographicsOctreotide LAR

30 mg (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 load0%0–10%10–25%25–50%50%

16.759.57.1

11.94.8

11.662.84.79.3

11.6

14.161.25.9

10.68.2

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

PROMID PROMID

Octreotide LAR 30 mg Extends TTP in Patients with Functioning and Non-functioning 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]

Pro

po

rtio

n w

ith

ou

t p

rog

res

sio

n

P=0.0007; HR=0.23 [95% CI: 0.09–0.57]

Pro

po

rtio

n w

ith

ou

t p

rog

res

sio

n

Patients with non-functioning tumours Patients with functioning tumours

Time (months)Time (months)

Octreotide LAR 30 mg: 17 pts / 11 events

Median TTP 14.26 months

Placebo: 16 patients / 14 events


Octreotide LAR 30 mg: 25 pts / 9 events


Placebo: 27 patients / 24 events


Arnold R. Abst #4508 presented at ASCO 2009, Orlando FLRinke A et al. J Clin Oncol 2009;27:4656–4663

Phase III Randomized Trial of Everolimus Phase III Randomized Trial of Everolimus (RAD001) vs Placebo in Advanced (RAD001) vs Placebo in Advanced

Pancreatic NETPancreatic NET (RADIANT-3) (RADIANT-3)

James YaoJames Yao11, Manisha Shah, Manisha Shah22, Tetsuhide Ito, Tetsuhide Ito33, , Catherine Lombard-Bohas Catherine Lombard-Bohas44, Edward , Edward

WolinWolin55, , Eric Van CutsemEric Van Cutsem66, David Lebwohl, David Lebwohl77, Sakina , Sakina HoosenHoosen77, Carolin Sachs, Carolin Sachs88, Jeremie Lincy, Jeremie Lincy88, ,

Timothy HobdayTimothy Hobday99 and Kjell Öberg and Kjell Öberg1010 for the RADIANT-3 study groupfor the RADIANT-3 study group

RADIANT-3 Study DesignRADIANT-3 Study Design

Everolimus 10 mg/d +best supportive care*

n = 207

Placebo +best supportive care*

n = 203

Multi-phasic CT or MRI performed every 12 weeks

Treatment until disease progression

Patients with advanced pNET, N = 410

Stratified by:•WHO PS•Prior Chemotherapy

Crossover

1:1

* Concurrent somatostatin analogs allowed

RANDOMIZE

Primary endpoint: • PFS (RECIST)

Secondary endpoints: • Response, OS, biomarkers, safety, and PK

Randomization August 2007 - May 2009

Phase III Double Blind Placebo Controlled Trial

Yao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9

PFS by Central Review* PFS by Central Review*

* Independent adjudicated central review committee• P-value obtained from stratified one-sided log rank test• Hazard ratio is obtained from stratified unadjusted Cox model

Kaplan-Meier medians PFSEverolimus: 11.4 monthsPlacebo: 5.4 months

Hazard ratio = 0.34; 95% CI [0.26-0.44]P-value: <0.0001

No. of patients still at riskEverolimusPlacebo

Per

cent

age

even

t-fr

ee


Overall SurvivalOverall SurvivalEverolimus 10mg

N = 207Placebo N = 203

No. of events – n (%) 51 (24.6%) 50 (24.6%)

HR = 1.05; 95% CI [0.71-1.55]; P = 0.594

No. censored – n (%) 156 (75.4%) 153 (75.4%)

Kaplan-Meier estimates [95% CI] at:

3 months 97.1 [93.6-98.7] 98.5 [95.5-99.5]

6 months 93.1 [88.7-95.9] 91.6 [86.8-94.7]

12 months 82.3 [76.0-87.0] 82.6 [76.5-87.3]

18 months 73.1 [65.1-79.6] 73.9 [66.1-80.2]

24 months 57.3 [43.0-69.2] 62.8 [51.1-72.4]

148 placebo patients crossed over to receive everolimus

Hazard ratio is obtained from the unadjusted stratified Cox modelP-value is obtained from the stratified one-sided log rank test


Everolimus provided a 65% reduction in risk for progression compared to placebo Everolimus provided a 65% reduction in risk for progression compared to placebo (HR = 0.35, (HR = 0.35, P P < 0.0001)< 0.0001)

• Everolimus therapy resulted in a significant 6.4 month increase in median Everolimus therapy resulted in a significant 6.4 month increase in median PFS PFS

– 4.6 months to 11.0 months4.6 months to 11.0 months

• 18 months PFS rate of 34% vs 9% placebo demonstrates that everolimus 18 months PFS rate of 34% vs 9% placebo demonstrates that everolimus provides a durable benefitprovides a durable benefit

Disease control rate (CR+PR+SD) was 77.7% with a significant response Disease control rate (CR+PR+SD) was 77.7% with a significant response difference, difference, PP < 0.0001 < 0.0001

Everolimus showed a consistent benefit in all subgroupsEverolimus showed a consistent benefit in all subgroups

Everolimus has an acceptable safety profileEverolimus has an acceptable safety profile

SummarySummary

Investigator, algorithmic, and central analysis of PFS showed a median Investigator, algorithmic, and central analysis of PFS showed a median difference in PFS of 5.9 to 7.2 months (HR, 0.32-0.42) favoring sunitinibdifference in PFS of 5.9 to 7.2 months (HR, 0.32-0.42) favoring sunitinib

The increase in PFS was not statistically significantThe increase in PFS was not statistically significant Though there is evidence of a clinically meaningful benefit, the magnitude of this Though there is evidence of a clinically meaningful benefit, the magnitude of this

benefit remains unclear due to the study being terminated earlybenefit remains unclear due to the study being terminated early These PFS results may be an overestimate because of early looks at the data and These PFS results may be an overestimate because of early looks at the data and

premature study terminationpremature study termination

The FDA did an additional analysis, and found a median PFS of 10.2 months The FDA did an additional analysis, and found a median PFS of 10.2 months for sunitinib and 5.4 months for placebo; these data were used in the Sutent for sunitinib and 5.4 months for placebo; these data were used in the Sutent prescribing informationprescribing information

There was no statistically significant improvement in OS There was no statistically significant improvement in OS (43% event rate; 69% crossover)(43% event rate; 69% crossover)

There was an increased risk for serious AEs associated with sunitinib, There was an increased risk for serious AEs associated with sunitinib, including 2 deaths from cardiac failureincluding 2 deaths from cardiac failure

Median exposure to treatment and follow up were 4.6 months and 10.2 Median exposure to treatment and follow up were 4.6 months and 10.2 months in the sunitinib arm and 3.7 months and 5.4 months in the placebo months in the sunitinib arm and 3.7 months and 5.4 months in the placebo armarm

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Sunitinib Phase III Trial: Sunitinib Phase III Trial: SummarySummary

The sunitinib trial and RADIANT-3 are both phase III, The sunitinib trial and RADIANT-3 are both phase III, randomized, double-blind studies that assessed the randomized, double-blind studies that assessed the effects of treatment on PFS in patients with advanced effects of treatment on PFS in patients with advanced pNETpNET

However, the trials differ substantially in design, patient However, the trials differ substantially in design, patient population, and study conduct and, therefore, can not be population, and study conduct and, therefore, can not be directly compareddirectly compared

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SummarySummary

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