Learning Objectives

• After completing this activity, participants should be able to:– Outline patient signs and symptoms that should lead to an

evaluation for NETs– Describe the diagnostic work-up that can confirm a

suspected diagnosis of NET– Review current treatment approaches for NETs and

expected patient outcomes– Analyze recent clinical trial data demonstrating improved

outcomes beyond symptom control in patients with advanced NETs

NET = neuroendocrine tumor

EpidemiologySigns and symptoms of NETs

NETs: A Not-So-Rare Disease

19731974197519761977197819791980198119821983198419851986198719881989199019911992199319941995199619971998199920002001200220032004

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

- N

ETs

Inci

denc

e pe

r 100

,000

– A

ll m

alig

nant

neo

plas

ms

All malignant neoplasms

Neuroendocrine tumors

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

Incidence of NETs Increasing

Colon Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary0

100

1100

1200

103,312 cases(35/100,000)

Case

s (t

hous

ands

)

29-year limited duration prevalence analysis based on SEER.Yao JC et al. J Clin Oncol. 2008;26:3063-3072.SEER = Surveillance, Epidemiology, and End Results

29-year limited duration prevalence analysis based on SEER.Yao JC et al. J Clin Oncol. 2008;26:3063-3072.SEER = Surveillance, Epidemiology, and End Results

NETs Are Second Most Prevalent Gastrointestinal Tumor

NET Prevalence in the US, 2004

Median survival (1988 – 2004)• Localized 203 months• Regional 114 months• Distant 39 months

Autopsy Studies

• Carcinoid1,2

– 2 studies • > 15,000 cases each

– 0.7% to 1.2%

• Islet cell3

– > 11,000 cases from Hong Kong

– 0.1%

1. Berge T, Linell F. Acta Pathol Microbiol Scand. 1976;84:322-330.2. Moertel CG et al. Cancer. 1961;14:291-293.3. Lam KY, Lo CY. Eur J Surg Oncol. 1997;23:36-42.

Vague abdominal symptoms

Primary tumor

Flushing

Metastases

Diarrhea

Death

NETs Are Often Diagnosed Late

TimeTime

Vinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.

Missed Symptoms and Late Diagnosis

50%

24%

27%

Localized RegionalDistant

• Flushing– No sweating– First sip of alcohol

• Diarrhea– Especially nocturnal

• Wheezing• Irritable bowel syndrome• Bloating

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

Pathologic confirmationAssess disease burdenAssess functional status

Diagnosis and Initial Work-Up

Anatomic Imaging: CT

Std

Venous Delayed

Arterial

Imaging studies property of James Yao, MD. CT: computed tomography.

Anatomic Imaging: MRI

MRI = magnetic resonance imagingImaging studies property of James Yao, MD.

Anatomic CT and Indium-111 Pentetreotide Scintigraphy

Imaging studies property of James Yao, MD.

Tumor Markers

• General NET markers– Chromogranin A• Affected by somatostatin analogues, proton pump

inhibitors, kidney function, liver function– Neuron-specific enolase

• Midgut (small bowel, appendix, cecum)– 5 HIAA (24-hr urine collection)– Serotonin (blood, more variable)

5-HIAA = 5-hydroxyindoleacetic acid

Other Markers in Functional Tumors

Fasting measurements when possible

Principles of Marker Assessment

• Lots of markers; expression can change over time– Chromogranin B and C, pancreastatin, substance P,

neurotensin, neurokinin A, pancreatic polypeptide• Take large panel of markers at key points

– Diagnosis or relapse• Follow a few elevated markers over time• Not necessary to check every marker at each visit

Somatostatin analogsChemotherapy for pancreatic NETsRegional therapy approaches

Current Treatment Approaches

Limited Options for Advanced NETs

Octreotide LAR + chemotherapy

Chemotherapy

Octreotide LAR

No standard

No standard

Functional

Nonfunctional

Midgut No syndrome

Non-midgut No syndrome

pNET

Carcinoid

Carcinoid syndrome

Dis

ease

pro

gres

sion

Hepatic artery embolization

Investigational agents

(No approved therapiesavailable)

LAR = long-acting release; pNET = pancreatic NET

pNET: Streptozocin-Based Chemotherapy

Imaging studies property of James Yao, MD.

• Median survival– Carcinoid 43 months– pNET 27 months

• Carcinoid– No approved drugs for tumor

control

• pNET– Streptozocin approved but

perceived to be toxic– No agreed-upon standard

treatment for tumor control

SurvivalPatients with distant NET (1988-2004)

Limited Options

Need for Tumor Control Agents Remains High

CarcinoidPancreatic NET

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

Somatostatin receptorPeptide receptor radiotherapyAngiogenesismTOR

Emerging Therapeutic Approaches

mTOR = mammalian target of rapamycin

Targeting NETs

• Somatostatin receptors highly expressed by NETs

– Targeting SST receptors can provide symptom and disease control

• New targets could change treatment paradigm :

– mTOR, PI3K, VEGF inhibitors– Other antiangiogenic agents

• High potential for combinations

PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor

PROMID: Octreotide LAR Slows Progression in Midgut NETs

Octreotide LAR vs placebo P = .000072HR = 0.34 [95% CI: 0.20–0.59]

Octreotide LAR (n = 42) Median 14.3 months

Placebo: (n = 43) Median 6.0 months

Time (months)

Prop

ortio

n w

ithou

t pro

gres

sion

0

0.25

0.5

0.75

1

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

Based on conservative ITT analysis

HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors; TTP = time to progression Rinke A et al. J Clin Oncol. 2009;27:4656-4663.

TTP in Midgut NET

No Standard

Potential Management of Advanced NETs Post-PROMID

Octreotide LAR + chemotherapy

Chemotherapy

Octreotide LAR

Consider octreotide LAR

No standard

Functional

Nonfunctional

Midgut No syndrome

Non-midgut No syndrome

pNET

Carcinoid

Carcinoid syndrome

Dis

ease

pro

gres

sion Investigational

agents

(No approved therapiesavailable)

• Systemic radiotherapy targeting somatostatin receptors

• Compounds vary by isotope and carrier molecule

• 177Lu DOTATATE1 and 90Y DOTATOC2: promising results in phase 2 studies

Peptide Receptor Radiotherapy (PRRT)111In pentetreotide

DTPA-CO-NH-D-Phe-Cys

S

S

Thr(ol)-Cys

Phe

D-Trp

Lys

Thr

111In

DOTA-CO-NH-D-Phe-Cys

S

S

Thr(ol)-Cys

Tyr

D-Trp

Lys

Thr

90Y DOTATOC

90Y

177Lu DOTATATE

DOTA-CO-NH-D-Phe-Cys

S

S

Thr-Cys

Tyr

D-Trp

Lys

Thr

177Lu

177Lu-DOTATATE:177Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid0 (DOTA), Tyr3-octreotate; 90Y DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide.1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130. 2. Waldherr C et al. Ann Oncol. 2001;12:941-944.

90Y-DOTATOC, 90Y-Edotreotide

• Multiple studies– Various doses: 6 GBq/m2, 7.4 GBq/m2,

13.3 GBq/m2

– Various schedules of 3-4 treatments

• RRs from smaller studies: 23%1 & 24%2

• RR from larger study (N = 90): 4.4%3

Waldherr C et al. J Nucl Med. 2002;43:610-616.Waldherr C et al. Ann Oncol. 2001;12:941-944.Bushnell DL et al. J Clin Oncol. 2010;28:1652-1659.

• N = 504 • 27.8-29.6 GBq in 4

cycles• Efficacy in 310 pts, NOT

ITT• RR: 30%• Median TTP: 40 months

177Lu DOTATATE Phase 2 Study

ITT = intent-to-treat; RR = response rate; TTP = time to progression Imaging studies property of James Yao, MD.Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130.

• If ITT principle applied to response:– 91 responses among 504 patients– RR drops to 18%

• High reported TTP calculated only for 249 who did not have PD as best treatment outcome• PRRT clearly active; strong need for rigorous

phase 3 study

177Lu DOTATATE: What Does It Mean?

PD = progressive diseaseKwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130.

NET: Bevacizumab fCT

Baseline

Day 2 after bevacizumab

Imaging studies property of James Yao, MD.

Bevacizumab: Randomized Phase 2 Trial

Stable dose of octreotide x 2 months

Random assignment

Bevacizumab + PEG interferon α-2b(+ octreotide)

Protocol starts here

Bevacizumab(+ octreotide)

PEG interferon α-2b(+ octreotide)

18 wks

Bevacizumab(n = 22)

PEG interferon(n = 22)

PR (confirmed)

4 0

SD 17 16

PD 1 6

ITT by assignment

P = .019 (2-sided exact)

Additional responses:•1 pt with PD on PEG interferon had PR after addition of bevacizumab•1 pt with SD on PEG interferon had PR after addition of bevacizumab

PR = partial response; SD = stable diseaseYao JC et al. J Clin Oncol. 2008;26:1316-1323.

Sunitinib: Phase 2 Open-Label Study

Carcinoid, n (%) (n = 41)

Islet cell, n (%) (n = 66)

All pts, n (%) (N = 107)

PR (confirmed) 1 (2) 11 (17) 12 (11)

SD 34 (83) 45 (68) 78 (73)

PD 1 (2) 5 (8) 6 (6)

Not evaluable 5 (12) 5 (8) 10 (9)

Kulke MH et al. J Clin Oncol. 2008;26:3403-3410.

Carcinoid: SWOG 0518 Phase 3 Study

Poor prognosis(N = 283)

Octreotide + interferon

Octreotide + bevacizumab

Supported by CTSUEndorsed by ECOG, CALGB, NCCTG

R

CALGB = Cancer and Leukemia Group B; CTSU = Cancer Trials Support Unit; ECOG = Eastern Oncology Cooperative Group; NCCTG = North Central Cancer Treatment Group; SWOG = Southwestern Oncology Group

Sunitinib Phase 3 pNET Study

Islet cell w/PD over prior 12 months (340 planned,

171 accrued)

Sunitinib 37.5 mg continuous dosing

Placebo

Stopped early at unplanned time pointMarch 12, 2009

Investigator-reported PFS: 11.4 mo with sunitinib vs 5.5 mo with placebo

R

PFS = progression-free survivalRaymond E et al. ASCO GI 2010; Abstract 127.

mTOR Signaling Pathways

SOSGrb

Metabolism AngiogenesisGrowth & Proliferation

Nutrients &Metabolites

4EBP1

Rheb

Receptor Tyrosine Kinase

p70S6K

PI3K

IRS-1 RASPP

TSC1/2

AKT

eIF4E

Protein Synthesis

Cyclin D, p27

Glut 1 VEGF, PDGF-β

PP

HIF-1α

EverolimusmTORC1

Angiomyolipomas

Subependymal giant-cell astrocytoma Islet cell carcinoma

Imaging studies property of James Yao, MD.

MDACC: Everolimus + Octreotide LARResponse

Per protocol Overall

N = 60Carcinoid

n = 30Islet cell

n = 30

PR 13 (22%) 5 (17%) 8 (27%)

SD 42 (70%) 24 (80%) 18 (60%)

PD 5 (8%) 1 (3%) 4 (13%)

PFS (median) 60 wks 63 wks 50 wks

ITT RR: 20%

MDACC = M. D. Anderson Cancer Center; RR = response rate Yao JC et al. J Clin Oncol. 2008;26:4311-4318.

RADIANT-1: Study Design

• Advanced pancreatic NET with RECIST progression following cytotoxic chemotherapy

– Stratum 1: No octreotide LAR 60d before enrollment• Received everolimus 10 mg/d

– Stratum 2: Octreotide LAR ≥ 3mo before enrollment • Received everolimus 10 mg/d + octreotide LAR ( ≤ 30 mg, q28d)

Treatment until progression; CT or MRI at baseline & q3mo

Primary endpoint•RR stratum 1Secondary endpoints•RR stratum 2•Response duration•Safety•PFS•Survival•PK

Stratum 1 n = 115

SCREEN Stratum 2

n = 45

Everolimus +octreotide LAR

Everolimus

PK = pharmacokinetics; RECIST = Response Evaluation Criteria In Solid TumorsYao JC et al. J Clin Oncol. 2010;28:69-76.

RADIANT-1: Best Change from BaselineCentral Radiology Review

Stratum 1: Everolimus (n = 115)

Stratum 2: Everolimus + Octreotide LAR (n = 45)

Central radiology ITT, n (%)PR 11 (9.6)

SD 78 (67.8)

Clinical benefit (PR + SD)

89 (77.4)

PD 16 (13.9)

Unknown 10 (8.7)

Central radiology ITT, n (%)PR 2 (4.4)

SD 36 (80.0)

Clinical benefit (PR + SD)

38 (84.4)

PD 0 (0.0)

Unknown 7 (15.6)

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

RADIANT-1 PFS by Central Review

Everolimus Everolimus + octreotide LAR

84 6

n = 115

Median PFS = 9.7 mo 0

20

40

60

80

100

Prob

abili

ty (%

)

260 2 10 12 14 16 18 20 22 24

Time, mo5481 58 0115 111 36 25 15 12 5 3 3 1

Patientsat risk

24

0Patientsat risk

84 6

n = 45

Median PFS = 16.7 mo 0

20

40

60

80

100

Prob

abili

ty (%

)0 2 10 12 14 16 18 20 22

Time, mo

2132 2245 39 19 14 10 8 3 3 1

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

Octreotide LAR + Everolimus

Octreotide LAR + placebo

Advanced carcinoid with syndrome in

progression(N = 429)

Pivotal Phase 3 Trials with Everolimus in NETs

R

Accrual completed

Best supportive care + everolimus*

Best supportive care + placebo*

Advanced pNET in progression

(N = 410)R

Accrual completed

*Octreotide LAR included as best supportive care.*Octreotide LAR included as best supportive care.

Conclusions• NETs not that rare• Progress being made• Somatostatin analogs effective in controlling

hormonal syndrome• PROMID suggests octreotide LAR controls tumor

growth in midgut carcinoids• Phase 2: VEGF and mTOR inhibitors have single-agent

activity in NETs• Confirmatory phase 3 studies ongoing