1. Emerging Treatment Options in the Management of Neuroendocrine Tumors
Moderator:
Martyn Caplin, MD
Professor of Gastroenterology
University College London
Department of Gastroenterology
Royal Free Hospital
London, United Kingdom
Panel:
Eric Van Cutsem, MD, PhD
Professor of Internal Medicine
Digestive Oncology Department
University Hospital Gasthuisberg
Leuven, Belgium
Panel (cont):
Marianne Pavel, MD
Department of Gastroenterology, Hepatology, and Endocrinology
Charité Hospital
Berlin, Germany
Simron Singh, MD
Odette Cancer Centre
Sunnybrook Health Sciences Centre
Toronto, Canada

2. NETs: A Clinical Challenge
Heterogeneous group of cancers derived from hormone-producing cells of the diffuse endocrine system
Increasing incidence over past 3 decades
Reported prevalence up to 35 per 100,000
Frequently diagnosed at advanced stage
Early detection improves chance of surgical cure or prolonged palliation with therapy
NETs: neuroendocrine tumors
Yao JC, et al. J Clin Oncol. 2008;26:

3. Treatment Options in NETs
Surgery
Embolization
(± chemotherapy)
Medical treatment
Somatostatin analogues
Alpha interferon therapy
Chemotherapy
PRRT
Biologic targeted agents
PRRT: peptide receptor radionuclide therapy 3

4. Multidisciplinary Treatment for NETs
Multimodality treatment is optimal
Medical oncologists, surgeons, gastroenterologists, endocrinologists, interventional radiologists, nurses
Surgery and other local modality treatments
Includes radio-frequency ablation, liver-directed embolization, hepatic artery embolization
Systemic treatment
Includes SSAs, chemotherapy, biologic targeted agents
SSAs: somatostatin analogues

5. RADIANT-2: The Rationale for Combining Everolimus and Octreotide LAR
mTOR: central regulator of growth, proliferation, metabolism, and angiogenesis [a-c]
NETs linked to genetic alterations that activate the mTOR pathway [b,c]
Everolimus inhibits mTOR [c]
Octreotide downregulates IGF-1, an upstream activator of the PI3K/AKT/mTOR pathway [d]
Everolimus + octreotide LAR showed activity in a phase-2 trial [e]
LAR: long-acting release
a. O’Reilly T, et al. Transl Oncol. 2010;3: b. Meric-Bernstam F, et al. J Clin Oncol. 2009;27: c. Faivre S, et al. Nat Rev Drug Disc. 2006;5: d. Susini C, et al. Ann Oncol. 2006;17: e. Yao JC, et al. J Clin Oncol. 2008;26:

6. RADIANT-2 Phase 3 Double-Blind, Placebo-Controlled Trial: Study Design
Enrollment January 2007–March 2008
Everolimus 10 mg/d +
octreotide LAR 30 mg/28 days
n = 216
RANDOMI ZE
Patients with advanced NET and history of symptoms attributed to carcinoid syndrome, N = 429
1:1
Treatment until disease progression
Crossover
Placebo +
octreotide LAR 30 mg/28 days
n = 213
Primary endpoint:
PFS (RECIST)
Secondary endpoints:
Tumor response, OS, biomarkers, safety, PK
Multiphasic CT or MRI performed every 12 weeks
CT: computed tomography; MRI: magnetic resonance imaging; OS: overall survival;
PFS: progression-free survival; PK: pharmacokinetics; RECIST: Response Evaluation Criteria In Solid Tumors
Pavel M, et al. ESMO 2010; Abstract LBA 8. 6 6 6

7. RADIANT-2: PFS by Central Review*
Time (mo) 20 40 60 80
100 2 4 6 8 10 12 14 16 18 22 24 26 28 30 32 34 36 38
% Event-free
Total events = 223
Censoring times
E + O (n/N = 103/216)
P + O (n/N = 120/213)
Kaplan-Meier median PFS Everolimus + octreotide LAR: 16.4 months Placebo + octreotide LAR: 11.3 months
HR = 0.77; 95% CI (0.59–1.00)
P = .026
No. of patients still at risk
E + O
P + O
81 72
69 65
63 57
56 50
50 42
42 35
33 24
22 18
17 11
11 9
4 3
1 1
1 0
0 0
*Independent adjudicated central review committee; P value obtained from one-sided log-rank test;
HR obtained from unadjusted Cox model.
E + O: everolimus + octreotide LAR; HR: hazard ratio; P + O: placebo + octreotide LAR.
Pavel M, et al. ESMO 2010; Abstract LBA 8.

8. RADIANT-2: PFS by Local Investigator Review
% Event-free 20 40 60 80
100 2 4 6 8 10 12 14 16 18 22 24 26 28 30 32 34 36 38
Time (mo)
Kaplan-Meier median PFS Everolimus + octreotide LAR: months Placebo + octreotide LAR: 8.6 months
HR = 0.78; 95% CI (0.62–0.98)
P = .018
Total events = 284
Censoring times
E + O (n/N = 128/216)
P + O (n/N = 156/213)
No. of patients still at risk
E + O
P + O
81 75
74 72
68 64
62 56
51 50
40 41
32 27
24 21
18 11
11 10
4 4
2 1
1 0
0 0
P value obtained from the one-sided log-rank test.
HR obtained from unadjusted Cox model.
Pavel M, et al. ESMO 2010; Abstract LBA 8.

9. RADIANT-2: Summary
Everolimus + octreotide LAR prolonged median PFS by 5.1 mo (HR = 0.77; P = .026)
Did not reach statistical significance (prespecified at P = .0246)
Everolimus + octreotide LAR demonstrated benefit across all subgroups
Everolimus + octreotide LAR has an acceptable safety profile
HR: hazard ratio

10. RADIANT-3: Study Rationale
mTOR: central regulator of growth, proliferation, cellular metabolism, and angiogenesis [a-c]
mTOR pathway activation observed with genetic cancer syndromes associated with pNET [d]
TSC2, NF1, VHL
Dysregulation of mTOR pathway, PTEN, and TSC2, in sporadic pNET is associated with poor prognosis [e]
Everolimus demonstrated antitumour activity in pNET in two phase-2 studies [f,g]
NF1: neurofibromatosis-1; pNET: pancreatic NET; TSC2: tuberous sclerosis-2; VHL: von Hippel–Lindau disease
a. O’Reilly T, et al. Transl Oncol. 2010;3: b. Meric-Bernstam F, et al. J Clin Oncol. 2009;27:
c. Faivre S, et al. Nat Rev Drug Disc. 2006;5: d. Yao JC, et al. Pancreatic Endocrine tumours.
In: DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 8th Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: e. Missialgia E, et al. J Clin Oncol. 2010;28:
f. Yao JC, et al. J Clin Oncol. 2008;26: g. Yao JC, et al. J Clin Oncol. 2010;28:69-76.

11. RADIANT-3 Phase 3 Double-Blind, Placebo-Controlled Trial: Study Design
Everolimus 10 mg/d +
BSC*
n = 207
RANDOMI ZE
Patients with advanced pNET N = 410
Stratified by:
WHO PS
Prior chemotherapy
1:1
Treatment until disease progression
Crossover
Placebo +
BSC*
n = 203
Primary endpoint: PFS (RECIST)
Secondary endpoints: Response, OS, biomarkers, safety, and PK
Multi-phasic CT or MRI performed every 12 weeks
Randomization August 2007–May 2009
BSC: best supportive care; PS: performance status; WHO: World Health Organization
Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028. 11 11 11

12. RADIANT-3: PFS by Investigator Review
Kaplan-Meier median PFS
Everolimus: 11.0 months
Placebo: 4.6 months
HR = 0.35; 95% CI [ ] P < .0001
100 80 60
% Event-free 40 20
Censoring Times
Everolimus (n/N = 109/207)
Placebo (n/N = 165/203) 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Time (mo)
No. of patients still at risk
Everolimus
Placebo
207
203
189
177
153 98
126 59
114 52 80 24 49 16 36 7 28 4 21 3 10 2 6 1 2 1 1 1
P-value obtained from stratified one-sided log rank test
Hazard ratio is obtained from stratified unadjusted Cox model
Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028.

13. RADIANT-3: Subgroup PFS Analysis
Subgroups (n) HR
Median PFS (mo) E P
Investigator review (410)
0.35
11.0
4.6
Central review* (410)
0.34
11.4
5.4
Prior chemotherapy
Yes (89)
3.0
No (221)
0.41
11.1
5.5
WHO Performance Status
0 (279)
0.39
13.8
1 or 2 (131)
0.30
8.3
Age Group
< 65 years (299)
4.5
≥ 65 years (111)
0.36
4.9
Gender
Male (227)
Female (183)
0.33
3.3
Race
Caucasian (322)
10.8
Asian (74)
0.29
19.5
3.8
Region
America (185)
Europe (156)
0.47
Asia (69)
2.9
Prior long-acting SSA
Yes (203)
0.40
11.2
3.7
No (207)
Tumor grade
Well diff. (341)
10.9
Moderately diff.(65)
0.21
16.6
Favors Everolimus Favors Placebo
*Independent adjudicated central review
E = Everolimus 10 mg PO daily; P = Placebo
0.4
0.8 1
Hazard Ratio
Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30–July 3, 2010; Barcelona, Spain. Poster # O-0028.

14. RADIANT-3: Overall Survival
Everolimus 10 mg
n = 207
Placebo
n = 203
Events: n (%)
51 (24.6%)
50 (24.6%)
HR = 1.05; 95% CI (0.71–1.55); P = .594
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 model
P-value is obtained from the stratified one-sided log rank test
Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028.

15. RADIANT-3 Summary and Conclusions
RADIANT-3: largest randomized controlled trial ever completed in advanced pNET
Everolimus reduced risk of progression by 65% vs placebo (HR = 0.35, P < .0001)
Median PFS: 11.0 mo with everolimus vs 4.6 mo with placebo
Acceptable safety profile: stomatitis, rash, infection, infrequent pneumonitis
Everolimus should be considered a standard of care in advanced pNET

16. Progress in NET Treatment
Midgut NET: Phase 3 PROMID trial with octreotide LAR
Advanced NET: Phase 3 RADIANT-2 trial with addition of everolimus
Advanced pNET: Phase 3 trials with everolimus (RADIANT-3) and sunitinib
PROMID: Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors

17. PROMID: Octreotide LAR Slows Disease Progression in Midgut NETs
TTP in Midgut NET
Octreotide LAR vs placebo P < .001
HR: 0.34 (95% CI: 0.20–0.59)
Octreotide LAR (n = 42)
Median 14.3 months
Placebo (n = 43)
Median 6.0 months
Time (mo)
Proportion without progression
0.25
0.5
0.75 1 6 12 18 24 30 36 42 48 54 60 66 72 78
Based on conservative ITT analysis
HR: hazard ratio; ITT: intent-to-treat; TTP: time to progression
Rinke A, et al. J Clin Oncol. 2009;27:

18. Phase 3 Trial: Sunitinib vs Placebo in Advanced pNET
Study halted prior to complete accrual due to treatment benefit
Unplanned Kaplan-Meier PFS analysis
1.0
P < .001; HR: (95% CI: to 0.649)
0.8
0.6
Sunitinib: PFS 11.1 mo
Survival probability
0.4
Placebo: PFS 5.5 mo
0.2
Sunitinib
Placebo
Efficacy endpoint variable value (mo)
Placebo, n
Sunitinib, n
Raymond E, et al. Presented at ESMO-GI 2009: Abstract 0013.

19. Ongoing Issues in NET Treatment
Predicting treatment efficacy/individualizing treatment
Drug approvals and insurance: access to treatment options
Combination regimens
Balancing toxicity and efficacy

20. Ongoing Issues in NET Treatment, cont’d.
Impact of treatment on quality of life
EORTC QOL questionnaire for NETs
Treatment selection: monotherapies vs combination regimens
Adjuvant therapy
EORTC: European Organization for Research and Treatment of Cancer

21. Conclusions
NETs: A heterogeneous group of tumors for which multiple therapeutic options are available
Treatment should be individualized by multidiscliplinary teams
Exciting new trial data with octreotide LAR, everolimus, and sunitinib
Ongoing clinical trial programs will provide additional clarity to treatment decisions