New Frontiers in Neuroendocrine Tumors

Treatment Carlos Frederico Pinto

Instituto de Oncologia do ValeHospital Regional do Vale do Paraiba

2008

Neuroendocrine Tumors -Background

Carcinoid, islet cell carcinomaSlow growing, often metastatic at diagnosisAssociated with carcinoid syndrome caused by hypersecretion of biogenic amines, peptides and polypeptides and manifested mainly with diarrhea and flushingSymptoms are treated with somatostatinanalogues (Octreotide & Lanreotide)

Somatostatin analogues

Octreotide

High binding affinity for the somatostatinreceptor subtype sst2, and low affinity for sst3and sst5 receptorsMany patients respond to Octreotide but subsequently experience tachyphalyxis after 12-18 monthsMay be due to downregulation of sst2 receptors on tumor cells or overexpression of other somatostatin receptors

OCTREOTIDEMECHANISMS OF ACTION

Affinity to SST-2 A & B receptors

Indirect effects:Inhibition of hormone secretion (GF, insulin, prolactin, intestinalpeptid)

Inhibition of growth factor secretion (IGF, Somatomedines 1 and2, EGF, PDGF, TGF-alfa)

Inhibition of angiogenesis

Immunomodulation

Direct effectAntimitotic

Induction of cell death (at high doses)

Lamberts et al. Endocrinol Rev 1991;12:450-82

SOMATOSTATIN ANALOGUES

Octreotide – Sandostatin ®Sandostatin LAR ®

Lanreotide – Somatuline ®

SOM-230 – Pasireotide

RC-160 – Vapreotide – Octastatin ®

OCTREOTIDE FOR TREATMENT OF NET

Somatostatin analogues provide:

Symptomatic response: 70 %

Biochemical response: 30-50 %

Tumor control: 3 %

Di Bartolomeo, Cancer, 1996.

SOMATOSTATIN ANALOGUES

Natural somatostatin has a half-life of 3 minutes.

Rebound phenomenon can be observed in withdrawal.

Sandostatin (octreotide) is a long acting analogue with a half-life of 100 minutes and can be used sc/iv.

Sandostatin LAR (long acting, repeatable) is a depot form usedintramuscularly every 3-4 weeks

Study No.of pts

Treatment Symptomaticresponse

Tumorregression

TomasettiAliment PharmacolTher 2000

16 Ocreotide LAR 20 mg

15/16 0 (14 SD, 2 PD)

OCTREOTIDE – ADVERSE EVENTS

Flatulance

Nausea-vomitting

Abdominal pain

Diarrhea

Lipid malabsorption

Biliary malfunction

Cholelitiasis

Vitamin D malabsorption

Injection site pain

Hypothyroidism

Hypo/hyperglycemia

Cardiac arrithmiasThe dose should be adjusted in patients using insulin, oral hypoglicemicagents, beta blocker and calcium channel blockers

tachyphalyxis after 12-18 months

USE OF OCTREOTIDE IN NETs

SC for 2 weeks

If tolerated and provides symptom relief:

Sart Sandostatin LAR at 20 mg i.m. / Every 4 week

SC form should be continued for another 2 weeks

Patient should be reevaluated 3 months later

If symptoms are under control patient can be treated with 10 mgSandostatin LAR every 4 weeks

İf symtoms are persisitant the dose can be increased to 30 mg

SC sandostatin can be used as salvage

Combination of Interferon + Octreotide

Response rateObjective response

CR : % 0PR : % 0SD : % 75PD : % 25

Biochemical responseCR : % 0PR : % 77SD : % 18PD : % 5

Tiensuu Eur J Cancer 1992;28A:1647-50

Abstract 171Safety and Efficacy of Pasireotide

(SOM230) in Patients with MetastaticCarcinoid Tumors Refractory or

Resistant to Octreotide LAR: Results of a Phase II Study

L. Kvols, M.D.H. Lee Moffitt Cancer Center and Research

Institute

Pasireotide (SOM230)

Novel, multi-ligand somatostatin analogueHigh affinity binding to four of the five somatostatin receptor subtypes: sst1, sst2, sst3 & sst5Compared to Octreotide has a 30-, 5- and 40- times greater affinity for sst1, sst3 & sst5 & comparable affinity for sst2

Study Design

Phase II, multicenter, open labelPatients with carcinoid symptoms refractory to Octreotide LARPasireotide 300mcg SQ bidDoses escalated to 1200mcg SQ bid

Safety & Tolerability

Adverse Event Total (n)Related to

Study Drug (n)

1293

Vomiting 3 23Fatigue 10

Nausea 12Abdominal Pain 14Diarrhea 10

+ Weight loss & hyperglycemia

Results – Symptom Control12/44 Patients with improvements in either BM/day and/or No. of flushing episodes/day

Pasireotide - Conclusions

Effective in controlling carcinoid symptoms in 27% patients refractory to Octreotide

Well tolerated with a safety profile similar to Octreotide

TUMOR TARGETED RADIOACTIVE SOMATOSTATIN TREATMENT

Alpha-emitting radioligands

Short acting auger electrons are used

111 In-pentetreotide

Beta-emitting radioligands

High energy beta particules

90Y-DOTA0 Tyr3-octreotide (OctreoTher)

177Lu-DOTA0 Tyr3-octreotate

90Y-lanreotide

Can only be used in sst2 and sst5 (+) NET

de Herder et al, Curr Opin Oncol, 2002

New agents

mTOR

TKI

Abstract 178Phase II Study of RAD001 (Everolimus)

and Depot Octreotide (SandostatinLAR) in Patients with Advanced Low Grade Neuroendocrine Carcinoma

J. C. Yao, M.D.University of Texas, M.D. Anderson Cancer Center

ASCO 2007

NET - RAD001

Octreotide LAR 30mg IM q28 days + RAD001 5mg PO daily26 patients (16 carcinoids, 11 islet cell)4 PR and 19 SD, 10 ↓ CgAToxicity

Mild apthous ulcerationG3/4: anemia, thrombocytopenia, apthousulcer, diarrhea, edema, fatigue, hypoglycemia, nausea, pain, rash

Phase 2 Study of RAD001 andDepot Octreotide

Single-arm phase 2Metastatic or unresecatable well-differentiatedNETRAD001 dose

Patient 1-30: 5mg dailyPatient 31-60: 10 mg dailySandostatin LAR 30mg IM 28d At 12 weeks, CT/MRI

Yao J. et al. PASCO 25:198 , 2007 (#4503)

Gary K. Schwartz, ASCO 2007

Study objectives

Assess objective tumor response rate as defined by RECIST

Assess PFSAssess biochemical response rateAssess safety of RAD001 at 5 and 10mg per day with Sandostatin LAR 30mg every4 weeks

Yao J. et al. PASCO 25:198 , 2007 (#4503)

Efficacy (RECIST):by tumor type:

OverallN = 60

CarcinoidN=30

Islet cellN=30

PR 12 (20%) 4(13%) 8(27%)

SD 43(72%) 25(83%) 18(60%)

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

MedianPFS

59 wks 64 wks 50 wks

Yao J. et al. PASCO 25:198 , 2007 (#4503)

Compare mTOR with sandostatinalone response

Carcinoid Islet cell Overall

RAD001 + sandoLAR(Yao, ASCO 2007)

4/30(13%) 8/30(27%) 12/60(20%)

Phase II Temsirolimus(Duran, BJC 2006)

1/21(5%) 1/15(7%) 2/37(5%)

Phase II Sando LAR(Wymenga, JCO 1999)

2/28(8%) 0/5(0%) 2/31(6%)

Why it works?

IGF-1 and IGF-1R are expressed and IGF-1 activates AKT and mTOR Pathways in NET cells

Wichert G, Cancer Res, 2000. RAPALOGs blocks signaling pro growth, proliferation and survival:

RapamycinRAD001CCI-779

Gary K. Schwartz, ASCO 2007

Gary K. Schwartz, ASCO 2007

Gary K. Schwartz, ASCO 2007

Gary K. Schwartz, ASCO 2007

Gary K. Schwartz, ASCO 2007

Gary K. Schwartz, ASCO 2007

Gary K. Schwartz, ASCO 2007

Gary K. Schwartz, ASCO 2007

Rationale for combinationmTOR inhibition activates AKT, a survivalpathway by a negative feedback loop.Sandostatin LAR normalizes IGF-1 levels in patients with acromegalySandostatin inhibits AKT in the exocrinepancreas.So...

Sandostatin should block ATK activation by “Rapalogues”

IGF-1R Inhibitors

SandostatinIMC-A12: MoABBMS-536924: TKICP751,871: MoABR1507: MoAB

Sorafenib in NETs – Background

NETs overexpress VEGF,VEGF-R, PDGF and PDGF-BOverexpression of VEGF associated withinferior PFSIncreased Ki-67 is associated with inferior outcome

Hobday T, PASCO 25:198 , 2007 (#4504)

Eligibility

Well or moderatily differentiated NETThyroid, Pheoc. and adrenal excludedMeasurable diseaseECOG PS 0-2<= prior chemotherapy

Prior embolization allowedNo prior antiangiogenic therapyPrior or concurrent octreotide allowed

Hobday T, PASCO 25:198 , 2007 (#4504)

Design

Sorafenib 400mg po BIDPrimary endpoint is confirmed PR byRECIST criteriaSecondary endpoints:

Minor responseProgression free at 6 monthsMedian PFS, OSToxicity

Two stage Phase IIHobday T, PASCO 25:198 , 2007 (#4504)

Results: objective response

TotalN=77

CTN=42

ICCN=35

Confirmed PR(any PR)

9%(12%)

7%(7%)

11%(17%)

Confirmed MR(20-29% decrease)

10% 7% 14%

Hobday T, PASCO 25:198 , 2007 (#4504)

Results: progression and survival

Median follow up for survivors 8.5 months65% progression free at 6 months

CT =58%ICC = 72%

16 have died, OS not matureBiochemical response:

6 out of 13 with CT had reduction in 5-HIAA

Hobday T, PASCO 25:198 , 2007 (#4504)

Translational Results: VEGFRsVEGFR

0-1+VEGFR

2-3+p-value

VEGFR2% responders (PR)

33%(4/12)

7.4%(2/27)

0.06

VEGFR3% responders (PR)

18.2%(4/22)

5.9%(1/17)

0.36

Ki67 <2% Ki67 >2%

% responders (PR) 0.0% 22.2%(6/27)

0.08

Hobday T, PASCO 25:198 , 2007 (#4504)

Efficacy of VEGF PathwayInhibitors in Neuroendocrine

Tumors

Agent Target Patients

Tumor response rate

(%)Median

PFS

Sunitinib 1

VEGFR,PDGFR, c-Kit,

RET41 carc

61 (PET)215

4233

Bevacizumab 2 VEGF 18 carcin 17 NR

1. Kulke et al, Proc ASCO 2005 A40082. Yao et al, Proc ASCO 2005 A4007

New agents

Temozolomide

Bevacizumab

Kulke MH, PASCO 25:198 , 2007 (#4505)

Kulke MH, PASCO 25:198 , 2007 (#4505)

Kulke MH, PASCO 25:198 , 2007 (#4505)

Kulke MH, PASCO 25:198 , 2007 (#4505)

Kulke MH, PASCO 25:198 , 2007 (#4505)

Kulke MH, PASCO 25:198 , 2007 (#4505)

Kulke MH, PASCO 25:198 , 2007 (#4505)

ADVANCES IN NETS TREATMENT AT A GLANCE

PARTIAL RESPONSESMINOR RESPONSESPROLONGATION OF PSF(RECIST)

Bevacizumab + temozolomide

Bevacizumab

Temozolomide

Sorafenib

Sunitinib

Temsirolimus

Everolimus (RAD001)

DISEASE STABILIZATION OR PROLONGING PFS:

Bortezomib

Pasireotide (SOM-230)

POSSIBLE STABILIZATION

Endostatin

Thalidomide

Gefinitib

Imatinib

CONCLUSIONSignificant progress has been observed in thetreatment and understanding of the pathobiologyand genetics of these neoplasms.

New drugs with multiple mechanisms of action

have significant activity, with improvements in

response and PFS in phase II trials

Several phase III trials are accruing patients using

mTOR and TK inhibitors agents.

It´s a “work in progress”....