This document summarizes recent advances in the treatment of neuroendocrine tumors. Several new agents have shown promising results in phase II trials, including pasireotide for tumors resistant to octreotide, everolimus combined with octreotide, sorafenib, sunitinib, and temsirolimus. These agents have multiple mechanisms of action and have led to partial responses and prolonged progression-free survival in early studies. While significant progress has been made, treatment of neuroendocrine tumors remains a work in progress as several phase III trials are currently evaluating mTOR and tyrosine kinase inhibitors.

1. New Frontiers in
Neuroendocrine Tumors
Treatment
Carlos Frederico Pinto
Instituto de Oncologia do Vale
Hospital Regional do Vale do Paraiba
2008

2. Neuroendocrine Tumors -
Background
Carcinoid, islet cell carcinoma
Slow growing, often metastatic at diagnosis
Associated with carcinoid syndrome caused by
hypersecretion of biogenic amines, peptides and
polypeptides and manifested mainly with
diarrhea and flushing
Symptoms are treated with somatostatin
analogues (Octreotide & Lanreotide)

3. Somatostatin analogues

4. Octreotide
High binding affinity for the somatostatin
receptor subtype sst2, and low affinity for sst3
and sst5 receptors
Many patients respond to Octreotide but
subsequently experience tachyphalyxis after 12-
18 months
May be due to downregulation of sst2 receptors
on tumor cells or overexpression of other
somatostatin receptors

5. OCTREOTIDE
MECHANISMS OF ACTION
Affinity to SST-2 A & B receptors
Indirect effects:
Inhibition of hormone secretion (GF, insulin, prolactin, intestinal
peptid)
Inhibition of growth factor secretion (IGF, Somatomedines 1 and
2, EGF, PDGF, TGF-alfa)
Inhibition of angiogenesis
Immunomodulation
Direct effect
Antimitotic
Induction of cell death (at high doses)
Lamberts et al. Endocrinol Rev 1991;12:450-82

6. SOMATOSTATIN
ANALOGUES
Octreotide – Sandostatin ®
Sandostatin LAR ®
Lanreotide – Somatuline ®
SOM-230 – Pasireotide
RC-160 – Vapreotide – Octastatin ®

7. OCTREOTIDE FOR
TREATMENT OF NET
Somatostatin analogues provide:
Symptomatic response: 70 %
Biochemical response: 30-50 %
Tumor control: 3%
Di Bartolomeo, Cancer, 1996.

8. 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 used
intramuscularly every 3-4 weeks
Study No.of Treatment Symptomatic Tumor
pts response regression
Tomasetti 16 Ocreotide LAR 15/16 0 (14 SD, 2 PD)
Aliment Pharmacol 20 mg
Ther 2000

9. OCTREOTIDE – ADVERSE EVENTS
Flatulance
Nausea-vomitting
Abdominal pain tachyphalyxis after
Diarrhea 12-18 months
Lipid malabsorption
Biliary malfunction
Cholelitiasis
Vitamin D malabsorption
Injection site pain
Hypothyroidism
Hypo/hyperglycemia
Cardiac arrithmias
The dose should be adjusted in patients using insulin, oral hypoglicemic
agents, beta blocker and calcium channel blockers

10. 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 mg
Sandostatin LAR every 4 weeks
İf symtoms are persisitant the dose can be increased to 30 mg
SC sandostatin can be used as salvage

11. Combination of Interferon +
Octreotide
Response rate
Objective response
CR : %0
PR : %0
SD : % 75
PD : % 25
Biochemical response
CR : %0
PR : % 77
SD : % 18
PD : %5
Tiensuu Eur J Cancer 1992;28A:1647-50

12. Abstract 171
Safety and Efficacy of Pasireotide
(SOM230) in Patients with Metastatic
Carcinoid 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

13. Pasireotide (SOM230)
Novel, multi-ligand somatostatin analogue
High affinity binding to four of the five
somatostatin receptor subtypes: sst1, sst2,
sst3 & sst5
Compared to Octreotide has a 30-, 5- and
40- times greater affinity for sst1, sst3 &
sst5 & comparable affinity for sst2

14. Study Design
Phase II, multicenter, open label
Patients with carcinoid symptoms
refractory to Octreotide LAR
Pasireotide 300mcg SQ bid
Doses escalated to 1200mcg SQ bid

15. Safety & Tolerability
Related to
Adverse Event Total (n) Study
Drug (n)
Nausea 12 12
Abdominal Pain 14 9
Diarrhea 10 3
Vomiting 3 2
Fatigue 10 3
+ Weight loss & hyperglycemia

16. Results – Symptom Control
12/44 Patients with improvements in either BM/day and/or No.
of flushing episodes/day

17. Pasireotide - Conclusions
Effective in controlling carcinoid symptoms
in 27% patients refractory to Octreotide
Well tolerated with a safety profile similar
to Octreotide

18. 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

19. New agents
mTOR
TKI

20. Abstract 178
Phase II Study of RAD001 (Everolimus)
and Depot Octreotide (Sandostatin
LAR) in Patients with Advanced Low
Grade Neuroendocrine Carcinoma
J. C. Yao, M.D.
University of Texas, M.D. Anderson Cancer Center
ASCO 2007

22. NET - RAD001
Octreotide LAR 30mg IM q28 days +
RAD001 5mg PO daily
26 patients (16 carcinoids, 11 islet cell)
4 PR and 19 SD, 10 ↓ CgA
Toxicity
Mild apthous ulceration
G3/4: anemia, thrombocytopenia, apthous
ulcer, diarrhea, edema, fatigue,
hypoglycemia, nausea, pain, rash

23. Phase 2 Study of RAD001 and
Depot Octreotide
Single-arm phase 2
Metastatic or unresecatable well-differentiated
NET
RAD001 dose
Patient 1-30: 5mg daily
Patient 31-60: 10 mg daily
Sandostatin LAR 30mg IM 28d
At 12 weeks, CT/MRI
Yao J. et al. PASCO 25:198 , 2007 (#4503)

24. Gary K. Schwartz, ASCO 2007

25. Study objectives
Assess objective tumor response rate as
defined by RECIST
Assess PFS
Assess biochemical response rate
Assess safety of RAD001 at 5 and 10mg
per day with Sandostatin LAR 30mg every
4 weeks
Yao J. et al. PASCO 25:198 , 2007 (#4503)

26. Efficacy (RECIST):
by tumor type:
Overall Carcinoid Islet cell
N = 60 N=30 N=30
PR 12 (20%) 4(13%) 8(27%)
SD 43(72%) 25(83%) 18(60%)
PD 5(8%) 1(3%) 4(13%)
Median 59 wks 64 wks 50 wks
PFS
Yao J. et al. PASCO 25:198 , 2007 (#4503)

27. Compare mTOR with sandostatin
alone response
Carcinoid Islet cell Overall
RAD001 + sando 4/30(13%) 8/30(27%) 12/60(20%)
LAR
(Yao, ASCO 2007)
Phase II 1/21(5%) 1/15(7%) 2/37(5%)
Temsirolimus
(Duran, BJC 2006)
Phase II 2/28(8%) 0/5(0%) 2/31(6%)
Sando LAR
(Wymenga, JCO
1999)

28. 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:
Rapamycin
RAD001
CCI-779

29. Gary K. Schwartz, ASCO 2007

30. Gary K. Schwartz, ASCO 2007

31. Gary K. Schwartz, ASCO 2007

32. Gary K. Schwartz, ASCO 2007

33. Gary K. Schwartz, ASCO 2007

34. Gary K. Schwartz, ASCO 2007

35. Gary K. Schwartz, ASCO 2007

36. Gary K. Schwartz, ASCO 2007

37. Rationale for combination
mTOR inhibition activates AKT, a survival
pathway by a negative feedback loop.
Sandostatin LAR normalizes IGF-1 levels in
patients with acromegaly
Sandostatin inhibits AKT in the exocrine
pancreas.
So...
Sandostatin should block ATK
activation by “Rapalogues”

38. IGF-1R Inhibitors
Sandostatin
IMC-A12: MoAB
BMS-536924: TKI
CP751,871: MoAB
R1507: MoAB

39. Sorafenib in NETs – Background
NETs overexpress VEGF,VEGF-R, PDGF
and PDGF-B
Overexpression of VEGF associated with
inferior PFS
Increased Ki-67 is associated with inferior
outcome
Hobday T, PASCO 25:198 , 2007 (#4504)

40. Eligibility
Well or moderatily differentiated NET
Thyroid, Pheoc. and adrenal excluded
Measurable disease
ECOG PS 0-2
<= prior chemotherapy
Prior embolization allowed
No prior antiangiogenic therapy
Prior or concurrent octreotide allowed
Hobday T, PASCO 25:198 , 2007 (#4504)

41. Design
Sorafenib 400mg po BID
Primary endpoint is confirmed PR by
RECIST criteria
Secondary endpoints:
Minor response
Progression free at 6 months
Median PFS, OS
Toxicity
Two stage Phase II
Hobday T, PASCO 25:198 , 2007 (#4504)

42. Results: objective response
Total CT ICC
N=77 N=42 N=35
Confirmed PR 9% 7% 11%
(any PR) (12%) (7%) (17%)
Confirmed MR 10% 7% 14%
(20-29% decrease)
Hobday T, PASCO 25:198 , 2007 (#4504)

43. Results: progression and survival
Median follow up for survivors 8.5 months
65% progression free at 6 months
CT =58%
ICC = 72%
16 have died, OS not mature
Biochemical response:
6 out of 13 with CT had reduction in 5-HIAA
Hobday T, PASCO 25:198 , 2007 (#4504)

44. Translational Results: VEGFRs
VEGFR VEGFR p-value
0-1+ 2-3+
VEGFR2 33% 7.4% 0.06
% responders (PR) (4/12) (2/27)
VEGFR3 18.2% 5.9% 0.36
% responders (PR) (4/22) (1/17)
Ki67 <2% Ki67 >2%
% responders (PR) 0.0% 22.2% 0.08
(6/27)
Hobday T, PASCO 25:198 , 2007 (#4504)

45. Efficacy of VEGF Pathway
Inhibitors in Neuroendocrine
Tumors
Tumor
response rate Median
Agent Target Patients (%) PFS
VEGFR,PDG
FR, c-Kit, 41 carc 2 42
Sunitinib 1 RET 61 (PET) 15 33
Bevacizumab 2 VEGF 18 carcin 17 NR
1. Kulke et al, Proc ASCO 2005 A4008
2. Yao et al, Proc ASCO 2005 A4007

46. New agents
Temozolomide
Bevacizumab

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

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

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

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

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

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

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

57. ADVANCES IN NETS
TREATMENT AT A GLANCE
DISEASE STABILIZATION PARTIAL RESPONSES
OR PROLONGING PFS: MINOR RESPONSES
PROLONGATION OF
Bortezomib
PSF(RECIST)
Pasireotide (SOM-230)
Bevacizumab + temozolomide
POSSIBLE
Bevacizumab
STABILIZATION
Temozolomide
Endostatin
Sorafenib
Thalidomide
Sunitinib
Gefinitib
Temsirolimus
Imatinib
Everolimus (RAD001)

58. CONCLUSION
Significant progress has been observed in the
treatment and understanding of the pathobiology
and 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”....