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

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

NETs: neuroendocrine tumors

Treatment Options in NETs

PRRT: peptide receptor radionuclide therapy

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

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]

a. O’Reilly T, et al. Transl Oncol. 2010;3:65-79. b. Meric-Bernstam F, et al. J Clin Oncol. 2009;27:2278-2287. c. Faivre S, et al. Nat Rev Drug Disc. 2006;5:671-688. d. Susini C, et al. Ann Oncol. 2006;17:1733-1742. e. Yao JC, et al. J Clin Oncol. 2008;26:4311-4318.

LAR: long-acting release

RADIANT-2 Phase 3 Double-Blind, Placebo-Controlled Trial: Study Design

Everolimus 10 mg/d + octreotide LAR 30 mg/28 days

n = 216

Placebo + octreotide LAR 30 mg/28 days

n = 213

Treatment until disease

progression

Patients with advanced NET and

history of symptoms attributed to

carcinoid syndrome, N = 429

1:1

Multiphasic CT or MRI performed every 12 weeks

Crossover

Primary endpoint: • PFS (RECIST)

Secondary endpoints: • Tumor response, OS, biomarkers,

safety, PK

Enrollment January 2007–March 2008

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.

RANDOMIZE

RADIANT-2: PFS by Central Review*

No. of patients still at riskE + OP + O

216213

202202

167155

129117

120106

102 84

8172

6965

6357

5650

5042

4235

3324

2218

1711

11 9

43

11

10

00

Kaplan-Meier median PFSEverolimus + octreotide LAR: 16.4 monthsPlacebo + octreotide LAR: 11.3 months

HR = 0.77; 95% CI (0.59–1.00) P = .026

Time (mo)

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

% E

vent

-fre

e

Total events = 223Censoring timesE + O (n/N = 103/216)P + O (n/N = 120/213)

Pavel M, et al. ESMO 2010; Abstract LBA 8.

*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.

RADIANT-2: PFS by Local Investigator Review

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.

No. of patients still at riskE + OP + O

216213

199201

167159

129121

119114

100 92

8175

7472

6864

6256

5150

4041

3227

2421

1811

1110

44

21

10

00

% E

vent

-fre

e

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

Time (mo)

Kaplan-Meier median PFSEverolimus + octreotide LAR: 12.0 monthsPlacebo + octreotide LAR: 8.6 months

HR = 0.78; 95% CI (0.62–0.98)P = .018

Total events = 284Censoring times

E + O (n/N = 128/216)P + O (n/N = 156/213)

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

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]

a. O’Reilly T, et al. Transl Oncol. 2010;3:65-79. b. Meric-Bernstam F, et al. J Clin Oncol. 2009;27:2278-2287. c. Faivre S, et al. Nat Rev Drug Disc. 2006;5:671-688. 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; 2008:1702-1721. e. Missialgia E, et al. J Clin Oncol. 2010;28:245-255. f. Yao JC, et al. J Clin Oncol. 2008;26:4311-4318. g. Yao JC, et al. J Clin Oncol. 2010;28:69-76.

NF1: neurofibromatosis-1; pNET: pancreatic NET; TSC2: tuberous sclerosis-2; VHL: von Hippel–Lindau disease

RADIANT-3 Phase 3 Double-Blind, Placebo-Controlled Trial: Study Design

Everolimus 10 mg/d +BSC*

n = 207

Placebo +BSC*

n = 203

Treatment until disease

progression

Patients with advanced pNETN = 410

Stratified by:• WHO PS• Prior chemotherapy

1:1

Multi-phasic CT or MRI performed every 12 weeks

Crossover

Primary endpoint: PFS (RECIST)

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

RANDOMIZE

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.

Randomization August 2007–May 2009

RADIANT-3: PFS by Investigator Review

• P-value obtained from stratified one-sided log rank test• Hazard ratio is obtained from stratified unadjusted Cox model

No. of patients still at riskEverolimus

Placebo207203

189177

153 98

126 59

114 52

8024

4916

36 7

28 4

21 3

10 2

61

21

01

Kaplan-Meier median PFSEverolimus: 11.0 months

Placebo: 4.6 months

HR = 0.35; 95% CI [0.27-0.45]P < .0001

01

00

Time (mo)

100

80

% E

vent

-fre

e

Censoring TimesEverolimus (n/N = 109/207)Placebo (n/N = 165/203)

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028.

Subgroups (n)HR

Median PFS (mo)

E PInvestigator review (410) 0.35 11.0 4.6Central review* (410) 0.34 11.4 5.4Prior chemotherapy Yes (89) 0.34 11.0 3.0 No (221) 0.41 11.1 5.5WHO Performance Status 0 (279) 0.39 13.8 5.4 1 or 2 (131) 0.30 8.3 3.0Age Group < 65 years (299) 0.39 11.0 4.5 ≥ 65 years (111) 0.36 11.1 4.9Gender Male (227) 0.41 11.0 4.6 Female (183) 0.33 11.0 3.3Race Caucasian (322) 0.41 10.8 4.6 Asian (74) 0.29 19.5 3.8Region America (185) 0.36 11.0 4.6 Europe (156) 0.47 10.8 4.6 Asia (69) 0.29 19.5 2.9Prior long-acting SSA Yes (203) 0.40 11.2 3.7 No (207) 0.36 10.8 4.9Tumor grade Well diff. (341) 0.41 10.9 4.6 Moderately diff.(65) 0.21 16.6 3.0

RADIANT-3: Subgroup PFS Analysis

Hazard Ratio

Favors Everolimus Favors Placebo

0 10.4 0.8

Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30–July 3, 2010; Barcelona, Spain. Poster # O-0028.

*Independent adjudicated central reviewE = Everolimus 10 mg PO daily; P = Placebo

RADIANT-3: Overall SurvivalEverolimus 10 mg

n = 207Placebo 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 modelP-value is obtained from the stratified one-sided log rank testYao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain.

Poster # O-0028.

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

Progress in NET Treatment

PROMID: Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors

PROMID: Octreotide LAR Slows Disease Progression in Midgut NETs

Octreotide LAR vs placebo P < .001HR: 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)

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

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

TTP in Midgut NET

HR: hazard ratio; ITT: intent-to-treat; TTP: time to progression

Placebo, n 79 25 6 1 0Sunitinib, n 74 32 14 2 0

1.0

Surv

ival

pro

babi

lity

0 5 10 15 20

Efficacy endpoint variable value (mo)

SunitinibPlacebo

Raymond E, et al. Presented at ESMO-GI 2009: Abstract 0013.

Phase 3 Trial: Sunitinib vs Placebo in Advanced pNET

Study halted prior to complete accrual due to treatment benefitUnplanned Kaplan-Meier PFS analysis

Sunitinib: PFS 11.1 mo

Placebo: PFS 5.5 mo

P < .001; HR: 0.397 (95% CI: 0.243 to 0.649)

0.8

0.6

0.4

0.2

0

Ongoing Issues in NET Treatment

• Predicting treatment efficacy/individualizing treatment

• Drug approvals and insurance: access to treatment options

• Combination regimens

• Balancing toxicity and efficacy

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

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