1. Toward More Aggressive Management of Neuroendocrine Tumors: Current and Future Perspectives Moderator: Ashley Grossman, MD, FRCP Professor of Neuroendocrinology William Harvey Research Institute Barts and the London School of Medicine and Dentistry St. Bartholomew's Hospital London, United Kingdom Panel: Eric Van Cutsem, MD Professor of Internal Medicine Digestive Oncology Department University Hospital Gasthuisberg Leuven, Belgium Panel (cont): Prof. Massimo Falconi, MD Department of Surgery University of Verona Verona, Italy Bertram Wiedenmann, MD, PhD Professor of Internal Medicine and Gastroenterology Chairman, Department of Hepatology, Gastroenterology, and Metabolic Diseases Charité Medical School, Campus Virchow-Klinikum Humboldt-University Berlin, Germany

2. 197319741975197619771978197919801981 19821983198419851986198719881989199019911992199319941995199619971998 199920002001200220032004 0.00 1.00 2.00 3.00 4.00 5.00 6.00 0 100 200 300 400 500 600 Incidence per 100,000 - NETs Incidence per 100,000 - All malignant neoplasms All malignant neoplasms Neuroendocrine tumors Yao JC, et al. J Clin Oncol. 2008;26:3063-3072. Incidence of NETs Increasing

3. ColonNeuroendocrineStomachPancreasEsophagusHepatobiliary 0 100 1100 1200 103,312 cases (35/100,000) Cases (thousands) Yao JC, et al. J Clin Oncol. 2008;26:3063-3072. NETs — Second Most Prevalent Gastrointestinal Tumor NET Prevalence in the United States, 2004 29-year limited duration prevalence analysis based on SEER [Surveillance, Epidemiology, and End Results].

4. Many NETs Are Diagnosed When Metastatic Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

5. Diagnostic Challenges in NET Heterogeneous group of tumors Wide variety of clinical presentations Late presentation Different terminology and classifications Histologic diagnosis may be difficult Variety of therapeutic options/approaches

6. Classification of NET Classification as functional vs nonfunctional Classification by site of origin Nearly identical characteristics on routine histologic evaluation, but different responses to therapeutic agents Classification by tumor stage TNM AJCC ENETS TNM: tumor, lymph nodes, metastasis; AJCC: American Joint Committee on Cancer; ENETS: European Neuroendocrine Tumor Society

7. Classification of NET (cont) Histologic classification Well-differentiated malignancies Highly aggressive malignancies: Poorly differentiated tumors with a high grade (grade 3) or Mitotic count > 20 per 10 HPFs, or Ki-67 proliferation index > 20% Molecular classification MEN 1 & 2, tuberous sclerosis, VHL HPF: high-power fields; MEN: multiple endocrine neoplasia; VHL: Von Hippel-Lindau disease

8. Grading Proposal for NETs of Ileum, Appendix, Colon, and Rectum GradeMitotic count (10 HPF)*Ki-67 index (%) † G1< 2≤ 2 G22–203–20 G3> 20 *10 HPF: 2 mm 2, at least 40 fields (at 40× magnification) evaluated in areas of highest mitotic density. † Ki-67, MIB1 antibody; % of 2000 tumor cells in areas of highest nuclear labeling. Rindi G, et al. Virchows Arch. 2007;451:757-762. HPF: high-power field

9. NET Survival by Histology Yao JC, et al. J Clin Oncol. 2008;26:3063-3072. 0 0.2 0.4 0.6 0.8 1.0 1224364860849610812072 Time (months) Survival Probability Median Survival Carcinoid / Islet cell Months95% CI Well differentiated124101 to 147 Unspecified grade129124 to 134 Moderately differentiated6456 to 72 Median Survival Neuroendocrine Months95% CI Poorly differentiated109 to 11 Anaplastic109 to 11 Unspecified grade109 to 11

10. Assessment of NET: Factors to Consider Clinical pictureHormonal peptides Imaging Anatomical imaging Molecular imaging SSR scanning Octreotide SPECT/CT New tracers (eg, 68Ga-DOTA- octreotide PET) Histology CT: computed tomography; PET: positive electron tomography; SPECT: single-photon emission computed tomography; SSR: somatostatin receptor

11. Treatment Goals in NET Total eradication by surgery Control of tumor growth Alleviation of clinical symptoms Improving and preserving quality of life

12. Factors in Treatment Decisions in NETs Treatment decisions require discussion by a multidisciplinary team Options may depend on: Type of NET TNM stage Tumor grade Extent of disease, including liver disease Functional status of tumor Patient: organ function, ECOG PS, comorbidity Access to various options ECOG: Eastern Cooperative Oncology Group; PS: performance status

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

14. Surgical Options in NET Radical surgery Complete resection of entire tumor even in presence of liver metastases Debulking surgery Always employed in functional carcinomas, when medical therapies do not control symptoms Resection of at least the primary tumor and liver metastases (suitable procedure when at least 90% of the tumor is resectable) Palliative surgery No resection Biliary, gastric, or digestive bypasses in case of obstruction when tumor is unresectable

15. Radical Surgery in NET: Consider Likelihood of Malignancy In absence of liver metastases or nearby structure invasion SiteBenignMalignant MidgutSame as in carcinoma; always considered to be malignant Pancreas Atypical resection: Enucleation Middle pancreatectomy Typical resection, same as in carcinoma: Pancreatic duodenectomy Left pancreatectomy

16. Debulking Procedures in NET Aims Reduce mechanical symptoms Preserve one target organ (the liver) for further therapies Improve survival “Weapons” Surgery TACE RFTA Combination of these procedures RFTA: radiofrequency thermal ablation; TACE: transarterial (chemo) embolization

17. Cumulative Survival Duration of follow up from date of diagnosis 0.0 0 Yrs 0.2 0.4 0.6 0.8 1.0 5 Yrs10 Yrs15 Yrs20 Yrs25 Yrs30 Yrs Primary removed Bowel bypass (n = 12) Failed resection (n = 17) No resection (n = 80) Resected (n = 210) Log rank (Mantel-Cox) P <.000 Prognosis and Clinical Course of Patients With Liver Metastatic Midgut NETs: A Retrospective European Study Ahmed A, et al. Endocr Relat Cancer. 2009;16:885-894. Survival of patients with bowel bypass vs failed resection, no resection, or resection

18. Challenges in Treatment of Metastatic NETs Over half of NET patients are diagnosed at metastatic stage [a] Metastatic NETs are incurable and most patients will succumb to the disease No new antitumor agents approved in the last 30 years Lack of level 1 evidence from controlled randomized trials to guide treatment of patients with NETs [a] Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

19. Symptomatic Treatment of NETs Symptoms of patients with metastatic NETs include: [a] – Diarrhea, flushing, bronchoconstriction, cardiac disease, hypoglycemia, gastric ulcer, skin rash 80% to 90% of patients with NETs express somatostatin receptors, which can be targeted [b] Somatostatin analogues effective in reducing hormonal secretion and controlling symptoms of NETs [a] – Most common adverse events: diarrhea, abdominal pain, nausea, flatulence, headache, cholelithiasis [a] Moertel CG. J Clin Oncol. 1987;5:1502–1522. [b] de Herder WW, et al. Endocr Related Cancer. 2003;10:451–458.

20. Complete or Partial Symptom Control With Octreotide LAR in NET Moertel CG. J Clin Oncol. 1987;5:1502–1522. 89% n = 49 n = 57 74% 68% n = 53 5% 25% 57% 050100 Urinary 5-HIAA Diarrhea Flushing Patients with improvement (%) > 50% improvement Complete improvement 5-HIAA: 5-hydroxyindoleacetic acid; LAR: long-acting release

21. PROMID: Phase 3 Randomized, Double-Blind, Placebo-Controlled Study in Midgut NETs Primary endpoint: TTP Secondary endpoints: Objective response rate, OS, quality of life, safety Patients with midgut NETs Treatment naive Histologically confirmed Locally inoperable or metastatic Well differentiated Measurable (CT/MRI) Functioning or nonfunctioning Octreotide LAR 30 mg IM every 28 days Placebo IM every 28 days RANDOMIZATION (1:1) Treatment until CT/MRI documented tumor progression or death CT: computed tomography; IM: intramuscular; MRI: magnetic resonance imaging; OS: overall survival; PROMID: Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors; TTP: time to progression Rinke A, et al. J Clin Oncol. 2009;27:4656-4663.

22. PROMID: Octreotide LAR Slows Disease Progression in Midgut NETs 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 (months) Proportion without progression 0 0.25 0.5 0.75 1 06121824303642485460667278 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

23. Systemic radiotherapy targeting somatostatin receptors Compounds vary by isotope and carrier molecule – Most common isotopes used are 90 Y-DOTATOC and 177 Lu-DOTATATE Positive somatostatin receptor scan required prior to treatment Promising results with Yttrium-90 edotreotide [1] and 177 Lu DOTATATE [2] in single-arm phase 2 trials No randomized controlled trials to date Peptide-Guided Radio Receptor Therapy (PRRT) [a] Bushnell DL, et al. J Clin Oncol. 2010;28:1652-1659 [b] Kwekkeboom DJ, et al. J Clin Oncol. 2008;26:2124-2130.

24. Systemic Chemotherapy in Pancreatic NET: Streptozocin and Temozolomide FU: fluorouracil; G1/2: grade 1/2; RR: response rate; SSA: somatostatin analogue Have shown ability to control symptoms and proliferation in G1/2 pancreatic NETs Considered second-line agents because of more side effects than first-line SSAs Combinations studied to date include: Streptozocin + 5-FU and/or doxorubicin Temzolomide + thalidomide, bevacizumab, or capecitabine Some combinations show promising RRs, but quality of existing data do not allow registration

25. Poorly Differentiated Neuroendocrine Carcinoma (NEC): Cisplatin + Etoposide Tumors mainly in upper GI and colon –Must be considered separately from other tumors –Treated similarly to SCLC Small studies (N = 18 to 41) with cisplatin + etoposide: [1,2] –Objective response similar to that in SCLC (42% to 54%) –Median survival also low (15 to 19 mo) [a] Moertel CG, et al. Cancer. 1991;68:227-232. [b] Mitry E, et al. Br J Cancer. 1999;81:1351-1355. SCLC: small-cell lung cancer

26. Rationale for the Use of Angiogenesis Inhibitors in NETs Dense vascularization is a key feature of NETs VEGF and VEGF-R are overexpressed in NETs Elevated circulating VEGF correlates with tumor progression Terris B, et al. Histopathology. 1998;32:133-138; Papouchado B, et al. Mod Pathol. 2005;18:1329-1335; Pavel M, et al. Clin Endocrinol. 2005;62:434-443; Welin S, et al. Neuroendocrinology. 2006;84:42-48; Zhang J, et al. Cancer. 2007;109:1478-1486. VEGF: vascular endothelial growth factor

27. Efficacy and Tolerability of Angiogenesis Inhibition in NETs Drug(s) Study PhaseTargetN PD entry criteria?RR PFS (months)AEs Drop-out rate Vatalanib 1 1/2 VEGFR-1,2,3 (PDGFR, c-kit) 23Yes 9% PR/MR 52% SD 7.535%: G3-432% Thalidomide 2 216No Ø PR 69% SD ND61%: G322% Endostatin 3 2endogenous inhibitor42No Ø PR 80% SD 5.8* 7.6 † 52%: G3-450% Sorafenib 4 2 C-RAF, B-RAF VEGFR- 2, -3, PDGFR-ß, KIT 82No 9% PR 10% MR SD not rep. 7.8 † 11.9* 43%: G3-465% Sunitinib 5 3VEGFR, PDGFR, c-kit86Yes 2.3% CR 7% PR 62.8% SD 11.426.5%:G3-4ND Bevacizumab + octreotide LAR 6 2VEGF + SSTR22No 18% PR 77% SD 5%: G3-4 36% (HTN) 5% 1. Pavel ME, et al. J Clin Oncol. 2008;26(May 20 suppl):14684. 2. Varker KA, et al. Cancer Chemother Pharmacol. 2008;61:661-668. 3. Kulke MH, et al. Clin Oncol. 2006;24:3555-3561. 4. Hobday TJ, et al. J Clin Oncol. 2007;25(June 20 suppl):4504. 5. Raymond E, et al. Presented at 2010 ASCO GI: Abstr 127. 6. Yao JC, et al. J Clin Oncol. 2008;26:1316-1323. *PNET; † GI NETs HTN: hypertension; MR: minor response; ND: not determined; PDGFR: platelet-derived growth factor receptor; PR: partial response; SD: stable disease; SSTR: somatostatin receptor; VEGFR: vascular endothelial growth factor receptor

28. Oral mTOR inhibitor with broad antitumor activity and antiangiogenic activity [a-d] Daily dosing with everolimus 5-10 mg resulted in continuous inhibition of mTOR activity [d,e] [a] Beuvink I, et al. Proc Am Assoc Cancer Res. 2001;42:366. Abstract 1972; [b] O’Reilly T, et al. Proc Am Assoc Cancer Res. 2002;43:71. Abstract 359; [c] O’Donnell A, et al. J Clin Oncol. 2008;26:1588-1595; [d] Tabernero J, et al. J Clin Oncol. 2008;26:1603-1610; [e] Tanaka C, et al. J Clin Oncol. 2008;26:1596-1602. Everolimus (RAD001): An Oral mTOR Pathway Inhibitor mTOR: mammalian target of rapamycin

29. RADIANT-1: RAD001 +/- Octreotide LAR in Pancreatic NET: Open-Label Phase 2 Study Everolimus 37.2% grade 3-4 AEs Everolimus + octreotide LAR 33.0% grade 3-4 AEs 846 n: 115 Median PFS: 9.7 mo 0 20 40 60 80 100 Probability (%) 26021012141618202224 Time (mo) 5481580115111362515125331 Patients at risk 24 0 Patients at risk 846 n: 45 Median PFS: 16.7 mo 0 20 40 60 80 100 Probability (%) 0210121416182022 Time (mo) 21322245391914108331 Yao JC, et al. J Clin Oncol. 2010;28:69-76. PFS by Central Review

30. RADIANT 3: BSC + Everolimus or Placebo in Progressive Advanced pNET P value obtained from stratified one-sided log-rank test HR obtained from stratified unadjusted Cox model Time (mo) Number of patients “at risk” Censoring times Everolimus (n/N = 109/207) Placebo (n/N = 165/203) Everolimus Placebo 207 203 189 177 153 98 126 59 114 52 80 24 49 16 36 7 28 4 21 3 10 2 6161 2121 0101 Kaplan-Meier median PFS Everolimus: 11.04 mo Placebo: 4.60 mo HR: 0.35 (95% CI 0.27 to 0.45) P <.0001 0101 0000 100 80 60 40 20 0 % of patients with progression 024681012141618202224262830 Yao J, et al. Ann Oncol. 2010;21(suppl 6): Abstract O-0028. Primary endpoint: PFS

31. Placebo, n7925610 Sunitinib, n74321420 1.0 0.8 0.6 0.4 0.2 0 Survival probability 05101520 Efficacy endpoint variable value (mo) Sunitinib Placebo 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 benefit Unplanned 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)

32. Medical Therapy in NETs: Summary Numerous agents now available Streptozocin and temozolomide have shown response in NETs – Lack strong evidence base Good data with everolimus, octreotide LAR, and sunitinib Options for poorly differentiated tumors: Oxaliplatin Cisplatin + etoposide

33. Future Directions Biomarkers and molecular imaging for evaluation of therapeutic response Personalized treatment based on molecular genetics and tumor biology WHO and TNM classification Molecularly targeted treatment will be the future: Targeted agents PRRT Combinations of traditional cytotoxics with targeted agents Combinations of targeted agents

34. Take-Home Messages Role of Pathology in NET Management Critical to appropriate management decisions in NETs Includes staging, grading, differentiation, site of origin, Ki-67 status, histologic characteristics Drives therapeutic strategy When to Consider Surgery Radical surgery should take priority when feasible Surgeon must coordinate with oncologist in advanced disease

35. When and How to Initiate Treatment in NETs Multidisciplinary decision-making process including pathologist Factors to consider include: – Where is primary site? – Progressive or stable disease? – Stage of disease? Take-Home Messages (cont)

36. Conclusions Precise pathology is crucial in management of NETs Surgical intervention is a key step in NET management, even when not curative Multidisciplinary team approach – Introduce treatment at appropriate time – Customize treatment based on patient and disease factors