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

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;26:3063-3072.

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

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] LAR: long-acting release 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.

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

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 216 213 202 202 167 155 129 117 120 106 102 84 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.

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: 12.0 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 216 213 199 201 167 159 129 121 119 114 100 92 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.

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] NF1: neurofibromatosis-1; pNET: pancreatic NET; TSC2: tuberous sclerosis-2; VHL: von Hippel–Lindau disease a. O’Reilly T, et al. Transl Oncol. 2010;3:65-79. 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.

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

RADIANT-3: PFS by Investigator Review Kaplan-Meier median PFS Everolimus: 11.0 months Placebo: 4.6 months HR = 0.35; 95% CI [0.27-0.45] 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.

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.

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.

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 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

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;27:4656-4663.

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: 0.397 (95% CI: 0.243 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 0 5 10 15 20 Efficacy endpoint variable value (mo) Placebo, n 79 25 6 1 0 Sunitinib, n 74 32 14 2 0 Raymond E, et al. Presented at ESMO-GI 2009: Abstract 0013.

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