Selection of Appropriate Treatment

Expert Review in Metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): Selection of Appropriate Treatment Reference Slide Deck

Neuroendocrine Tumors (NETs): A Diverse Group of Malignancies Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body 1 NETs can be functional or nonfunctional and include a heterogeneous group of neoplasms 2,3 Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 3 Islet cell tumors 2 Typical/atypical/poorly differentiated lung carcinoid 2 Small cell carcinoma of the lung 2,3 Pheochromocytoma/paraganglioma 2,3 Medullary thyroid carcinoma Merkel cell carcinoma 2,3 Kidney, bladder, breast, prostate, thymus 1. Caplin ME, et al. Lancet. 1998;352(9130):799-805. 2. NCCN Clinical Practice Guidelines in Oncology : Neuroendocrine Tumors V2.2016. Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed November 11, 2016. 3. Modlin IM, et al. Gastroenterology. 2005;128(6):1717-1751.

Incidence per 100 000 The Increasing Incidence of NETs 1.4 1.2 Lung and bronchus 1.0 0.8 Rectum Small intestine 0.6 0.4 0.2 0 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 Year Pancreas Stomach Cecum Colon Appendix Annual age-adjusted incidence of NETs in the US population by anatomic location Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.

The Gastrointestinal Tract (GI) Is the Most Common Primary Location of NET (US SEER Data) Percent distribution (%) Lung 17.2 Rectum 13.4 Jejunum/ileum Other/ unknown 15% 27% Digestive system 58% 6.4 Pancreas 6.0 Stomach 4.0 Colon 3.8 Duodenum 3.2 Cecum 3.0 Appendix 0.8 Liver Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.

1,200,000 NETs Are the Second Most Prevalent Type of GI Malignancy 1,100,000 2 times more prevalent than pancreatic cancer 100,000 0 Colorectal 1 GEP-NET 2 Stomach 1 Pancreas 1 Esophagus 1 Hepatobiliary 1 Prevalence in SEER Database 1. National Cancer Institute: SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/archive/csr/1975_2004/. Accessed: September 8, 2016. 2. Modlin IM, et al. Cancer. 2003;97(4):934-959.

Neuroendocrine Tumors (NETs) Are Heterogeneous With a Wide Spectrum of Characteristics Symptomatic Functioning Metastatic Poorly differentiated Indolent NET Aggressive Well-differentiated Localized Nonfunctioning Asymptomatic Öberg KE, et al. Cancer Metastasis Rev. 2011;30 Suppl 1:3-7.

NETs Are Often Advanced at the Time of Diagnosis Carcinoids M 1 at Dx SV 5 and M 1 Small intestine 70% 55% Colon 71% 20% Appendix 10% 34% Rectum 15% 30% Pancreatic NETs 50%-60% 30%-50% Median Survival, Years Well and moderately differentiated Local Regional Metastatic 2.75 2,75 9.25 9,25 18.5 18,5 Poorly differentiated metastatic 0,4 0.4 Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. 0 Soga J. Cancer. 5 2005;104(6):1180-1187. Alexiev 15 BA, et al. Diagn 20 Pathol. 2007;2:28. Modlin IM, et al. Lancet. 2008;9(1):61-72.

Survival Probability Correlation of Primary Tumor Site With Survival Known prognostic factors include: Distant metastases Location of primary tumor Extent of disease Tumor stage Degree of differentiation/ proliferative index 1.0 0.8 0.6 Colon Lung Pancreas Rectum Small bowel Tumor grade 0.4 Patient age Performance status 0.2 0 12 24 36 48 60 72 84 96 108 120 Time, months 65% of patients with advanced NETs will not be alive in 5 years Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.

Prognostic Value of Ki67 <2% 15% 75% Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798-7803. Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097. Scarpa A, et al. Mod Pathol. 2010;23(6):824-833. Grade Mitotic Count (10 HPF) Ki-67 Index (%) G1 2 2 G2 2-20 3-20 G3 20 20

Prognostic Value of Differentiation Histology Well- and moderately-differentiated histology Poorly differentiated histology Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.

High Complexity for NETs Classification Differentiation Grade Mitotic Count Ki67 Index Traditional ENETS; WHO Well differentiated Poorly differentiated Low grade (G1) Intermediate grade (G2) High grade (G3) <2 per 10 high power fields (HPFs) 2-20 per 10 HPFs >20 per 10 HPFs >20% Well-Differentiated 2% Carcinoid, islet cell, pancreatic (neuro)endocrine tumor 3%-20% Carcinoid, islet cell, pancreatic (neuro)endocrine tumor Small cell carcinoma Large cell neuroendocrine carcinoma Neuroendocrine tumor; grade 1 Neuroendocrine tumor; grade 2 Neuroendocrine tumor; grade 3, small cell Neuroendocrine tumor; grade 3, large cell Poorly-Differentiated Grade (ENETS) Low (G1) Intermediate (G2) High (G3) Ki67 index (%) 2 3-20 >20 Anatomic imaging Functional imaging Octreoscan SPECT or SSTR PET-positive More rapid growth on serial imaging FDG PET-positive Prognosis Indolent (slowly growing) Aggressive Bosman FT, eds. WHO Classification of Tumours of the Digestive System. 4 th Ed. Lyon, France: The International Agency for Research on Cancer; 2010. Rindi G, et al. Virchows Arch. 2006;449(4):395-401. Rindi G, et al. Virchows Arch. 2007;451(4)757-762. Jensen RT, et al. Neuroendocrinology. 2006;84(3):173-182.

Integrating Grade and Tumor Burden High Treatment goals: Tumor control and QoL Advanced, unresectable, well to moderately differentiated NETs: Primary treatment goals Tumor response/control & QoL Tumor response/control Rapid Tumor Response Tumor Burden QoL & tumor control Tumor control & QoL Tumor control/response Low QoL & tumor control Tumor control & QoL Tumor control & QoL Low Tumor Aggressiveness (eg, Ki67) Moderate (up to Ki67 = 20%)

Syndromes With Nonspecific Symptoms Caused by Hormones and Peptides Secreted by Functional NETs* NET Location Small bowel Pancreas Hormone /peptide Serotonin Gastrin Vasoactive intestinal peptide Insulin Glucagon Associated syndrome Carcinoid syndrome Zollinger- Ellison syndrome Verner-Morrison syndrome Hypoglycemia syndrome Cramping Wheezing Diarrhea Hypoglycemia Weight gain Rash Weight loss Flushing Ulcers Insulin resistance Glucose intolerance / diabetes *There are many other hormones, syndromes, and symptoms that can be caused by NETs. These are some of the most common. Modlin IM, et al. Lancet Oncol. 2008;9(1):61-72. Kaltsas GA, et al. Endocr Rev. 2004;25(3):458-511. Barakat MT, et al. Endocr Relat Cancer. 2004;11(1):1-18.

Carcinoid Syndrome Tumoral release of serotonin and other vasoactive substances into the systemic circulation causes carcinoid syndrome 1 Treatment with somatostatin analogs (SSAs) is associated with improved symptom control, but patients may not maintain adequate control of symptoms 2,3 Inhibition of serotonin synthesis with PCPA was previously shown to provide symptom control, but its utility was limited by CNS side effects 4 CNS, central nervous system; PCPA, parachlorophenylalanine 1. Kulke MH, et al. N Engl J Med. 1999;340(11):858-868. 2. Rubin J, et al. J Clin Oncol. 1999;17(2):600-606. 3. Strosberg, et al. Gastrointest Cancer Res. 2013;6(3):81-85. 4. Engelman K, et al. N Engl J Med. 1967;277(21):1103-1108.

Urinary 5-Hydroxyindoleacetic Acid (5-HIAA) Measured in a 24-hour urine specimen Arises in the setting of hepatic metastases or due to direct drainage into systemic circulation Severity of carcinoid syndrome may correlate with urinary 5-HIAA levels High levels have prognostic value and are associated with: - Reduced survival - Progressive carcinoid heart disease Kocha W, et al. Curr Oncol. 2010;17(3):49-64. Feldman JM, et al. Clin Chem. 1986;32(5):840-844. Formica V, et al. Br J Cancer. 2007;96(8):1178-1182. de Herder WW. Best Pract Res Clin Endocrinol Metab. 2007;212(1):33-41. Strosberg JR, et al. Clincal features of the carcinoid syndrome. Available at: www.uptodate.com. Last update: July 2015.

When to Treat? Factors to Consider in Nonfunctioning GI NETs Tumor factors to consider Signs and symptoms Pain, weight loss, etc Tumor volume What is the risk if tumor grows? Tumor aggressiveness Growth rate, Ki 67, marker levels Patient Functional status, organ function Preferences Risk from treatment Treatment factors Short-term risks, long-term risks Reversibility of AEs Risk from tumor progression

Treatment Options for NETs Surgery Debulking / Locoregional Therapy Resection of primary tumor Cytoreductive surgery of unresectable tumor Curative (rarely), ablative (very often) Radiofrequency ablation (RFA) Embolization / chemoembolization / radioembolization Medical Therapy Nuclear Medicine and Irradiation Somatostatin analogs (SSAs) Interferon-α Targeted therapies mtor inhibitors VEGFR inhibitors Other TKIs Chemotherapy Tumor-targeted, radioactive therapy: PRRT using, eg MIBG 90 Y-DOTATOC 177 Lu DOTATATE External irradiation (for bone, brainmetastases) Brachytherapy (for liver metastases) MIBG, meta-iodobenzylguanidine; mtor, mammalian target of rapamycin; PRRT, peptide-receptor radiotherapy; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor Salazar R, et al. Neuroendocrinology. 2012;95(2):71-73. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Neuroendocrine tumors. v2.2016. Available at: https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed October 7, 2016.

Factors Influencing the Therapeutic Decision in NETs Type of NET (pancreatic vs GI) TNM stage and grade (G1/G2 vs G3) Resectability Functioning vs nonfunctioning tumor Patient performance status and comorbidities Availability of different therapeutic modalities Uptake on somatostatin receptor scintigraphy Patient preference and convenience

ENETS Guidelines for 1 st -Line Treatment Drug Functionality Grading Primary Site SSTR status Special Considerations Octreotide +/- G1 Midgut + Low tumor burden Lanreotide +/- G1/G2 (~10%) Midgut, pancreas + Low and high (>25%) liver tumor burden IFN-alpha 2b +/- G1/G2 Midgut If SSTR negative STZ/5-FU +/- G1/G2 Pancreas Progressive in short-term* or high tumor burden or symptomatic; if STZ is contraindicated or not available TEM/CAP +/- G2 Pancreas Atypical carcinoid and/or SSTR negative Everolimus +/- G1/G2 Lung Insulinoma or contraindication for CTX Pancreas Insulinoma or contraindication for CTX Midgut If SSTR negative Sunitinib +/- G1/G2 Pancreas Contraindication for CTX PRRT +/- G1/G2 Midgut + (required) Cisplatin / etoposide Extended disease; extrahepatic disease, eg, bone metastasis +/- G3 Any All poorly differentiated NEC * 6-12 months; Cisplatin can be replaced by carboplatin Pavel M, et al. Neuroendocrinology. 2016;103(2):172-185.

Treatments New Options in NETs Treatment 1900 1980 2000 2005 2010 2015 1988/89 1998 2009 2014/15 2015/16 1982 STZ pnet 36 OCT SC CS 25,30 1992 STZ combination: Survival benefit pnet 2 LAN symptom control 24 OCT LAR carcinoid tumors 23,26,28 2010/11 PROMID OCT LAR: Antitumor activity 9,31 RADIANT-3 EVE in pnet 11,12,32,33 Sunitinib phase III pnet 13,31,34 CLARINET LAN GEP NET 16,17,29 ELECT LAN: Symptom control 27 RADIANT-4 EVE NF GI and lung NET 15,19 2015 TELESTAR telotristat etiprate CS 20 NDA filed 3/30/16 US approva l US/EU approva l EU approva l RADIANT-2 EVE + OCT, LAR in mnet w/cs 14 NETTER-1 177 Lu-Dotatate midgut NET 18 AC, atypical carcinoid; AJCC; American Joint Committee on Cancer; CS, carcinoid syndrome; ENETS, European Neuroendocrine Tumor Society; ESMO; European Society for Medical Oncology; EVE, everolimus; GEP, gastroenteropancreatic; GI NETs, gastrointestinal neuroendocrine tumors; LAN, lanreotide; LAR, long-acting repeatable; m, metastatic; NANETS, North American Neuroendocrine Tumor Society; NEC, neuroendocrine carcinomas; NET, neuroendocrine tumors; NF, nonfunctional; OCT, octreotide; pnet, pancreatic NET; SC, subcutaneous; STZ, streptozotocin; TC, typical carcinoid; UICC, Union for International Cancer Control; WHO, World Health Organization

Somatostatin Analogs Overview Synthetic derivatives of somatostatin 1 Bind to somatostatin receptors (SSTRs) 1 Similar to endogenous somatostatins but with 1 : Increased affinity for specific SSTRs Longer half-life and greater stability Octreotide and Lanreotide 2 SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 Pasireotide2 Longer duration of action in the body Have different SSTR affinity profiles 2 Octreotide and lanreotide have high affinity for SSTR2 and lower affinities for SSTR3 and SSTR5 Pasireotide has high affinity for SSTR1-3, and SSTR5 1. Susini C, et al. Ann Oncol. 2006;17(12):1733-1742. 2. Öberg KE, et al. Gastroenterology. 2010;139(3):742-753.

RANDOMIZATION (1:1) PROMID: Evaluation of the Antiproliferative Effect of Octreotide LAR 30 mg Phase III randomized, double-blind, placebo-controlled study Patients with midgut NETs Treatment naïve 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 Treatment until CT/MRI documented tumor progression or death Month 3 6 9 12 15 18 Primary endpoint: Time to tumor progression (blinded central review) Secondary endpoints: Objective response rate, survival, quality of life, safety CT, computed tomography; IM, intramuscular; MRI, magnetic resonance imaging Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663.

Proportion of Patients Without Progression Tumor Control in NET: Octreotide LAR Significantly Prolongs TTP PROMID: Well-differentiated midgut NET 66% reduction in the risk of tumor progression HR = 0.34; 95% CI: 0.20-0.59; P =.000072 1.00 0.75 0.50 Octreotide LAR 30 mg: 42 patients/26 events Median TTP = 14.3 months (95% CI 11.0-28.8) Placebo: 43 patients/40 events Median TTP = 6.0 months (95% CI 3.7-9.4) 0.25 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 HR, hazard ratio; TTP, time to progression Time, Months Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663.

Octreotide LAR 30 mg Achieved Superior Tumor Response at 6 Months (WHO) Octreotide LAR 30 mg (n = 42) Placebo (n = 43) Complete response, n 0 0 Partial response, n 1 1 Stable disease, n 28 16 Progressive disease, n 10 23 Unknown, n 3 3 WHO, World Health Organization Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663. Wilcoxon-Mann-Whitney test: P =.0079

Octeotride LAR: Safety Profile No treatment-related deaths Serious AEs (SAEs) were observed in 11 octreotide LAR treated and 10 placebo-treated patients Most common SAEs affected - GI tract (octreotide LAR, n = 6; placebo, n = 8) - Hematopoietic system (octreotide LAR, n = 5; placebo, n = 1) - General health status (fatigue and fever; octreotide LAR, n = 8; placebo, n = 2) Treatment discontinuation due to AEs occurred 5 octreotide LAR recipients and no placebo recipients WHO grade 2-4 adverse events were observed more often in the octreotide LAR arm and included diarrhea and flatulence Bile stones were recorded six times (octreotide LAR recipients n = 5) Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663.

Study design: CLARINET: Study Design Phase III, 96-week, randomized, double-blind, placebo-controlled, multicenter study (14 countries: United States, India, and 12 European countries) Primary endpoint: Progression-free survival, defined as time to disease progression or death Population: N = 204 adults with well or moderately differentiated, progressing, metastatic, and/or locally advanced unresectable GEP NETs, and Ki67 <10% Treatments: Lanreotide autogel 120 mg (fixed dose) vs placebo every 28 days Primary Endpoint = PFS 12-24 weeks Scan 1 Scan 2 1:1 Lanreotide autogel SC 120 mg q28 days Placebo SC q28 days 1 12 24 36 48 72 96 (baseline) PFS, progression-free survival Caplin ME, et al. N Engl J Med. 2014;371(3):224-233. Study Visits, Weeks

Patients Alive and With No Progression, % Tumor Control in NETs: Lanreotide Autogel Significantly Prolongs PFS CLARINET: Well/moderately differentiated nonfunctioning GEP NET 100 90 80 70 60 50 40 30 20 10 53% reduction in the risk of tumor progression HR = 0.47; 95% CI 0.30-0.73; P =.0002 Lanreotide Autogel 120 mg 32 events/101 patients Median, not reached Placebo 60 events/103 patients Median, 18.0 months (95% CI 12.1-24.0) 0 0 3 6 9 12 18 24 27 Time, Months Caplin ME, et al. N Engl J Med. 2014;371(3):224-233. 62% 22%

PFS According to Subgroups Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.

Lanreotide Autogel: Safety Profile Study Treatment-Related Adverse Events in 5% of Patients Event Lanreotide (n = 101) Placebo (n = 103) Diarrhea 26 (26) 9 (9) Abdominal pain 14 (14) 2 (2) Cholelithiasis 10 (10) 3 (3) Flatulence 8 (8) 5 (5) Injection-site pain 7 (7) 3 (3) Nausea 7 (7) 2 (2) Vomiting 7 (7) 0 Headache 5 (5) 2 (2) Lethargy 5 (5) 1 (1) Hyperglycemia 5 (5) 0 Decreased level of pancreatic enzymes 5 (5) 0 Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.

Trials Investigating Somatostatin Analogs Trial (Prospective/ Retrospective) Primary/ Number Prior SSA? Intervention Symptoms DCR ORR Biochemical Response Toxicity Anthony 1993 (P) NET (14) N Octreotide 500-2000 mcg tid lanreotide 750-3000 mcg tid N 46% 31% NA No major AE di Bartolomeo 1996 (P) SBNET/PN ET (58) N Octreotide 500 mcg tid (n = 23) or 1000 mcg tid (n = 35) Diarrhea improved in 40%, flushing in 50% 50% 3% 77% (u5hiaa) Gallstones (4%), Steatorrhea (4%) Filosso 2002 (P) Bronchial NET (7) N Octreotide 1500 mcg/d All improved 100% 42% 100% Nil Eriksson 1997 (P) SBNET/PN ET(19) N Lanreotide 750 mcg qid to 3 mg qid Flushing better (P =.06) NA NA 58% 4 ceased due to AE (gallstone, diarrhea) Faiss 1999 (P) Foregut NET (30) Y Lanreotide 5 mg tds Improved on the whole 36% 6% Decreased (CgA/u5HIAA) Fatigue (30%), steatorrhea (6%), cholelithiasis (3%) Strosberg 2014 (R) Metastatic NET (239) Y Octreotide 40-133 mg/month 70% to 80% reported improvement in flushing/diarrhea NA NA NA NA Welin 2004(P) Midgut NET (12) N Octreotide 160 mg/m 2 weeks NA 75% 0% CgA 33%, u5hiaa 16% Gallstone (8%), fever (50%) Al-Efraij 2014 (R) Metastatic NET (27) Y Octreotide 40-60 mg Diarrhea 62%, flushing 76%, palpitation 100% 29% 0% CgA 31%, u5hiaa 23% NA Weber 2012 (R) Metastatic NET (337) Y Octreotide 40-60 mg Diarrhea 62%, 56% flushing NA NA NA NA Modica 2015 (R) Metastatic NET (21) Y Octreotide LAR (15), lanreotide (6) 63% improved 53% 5% NA Abdominal discomfort (5%), gallstones (5%), T2DM (5%) Albertelli 2016 (P) Metastatic NET (35) Y Lanreotide ATG 180 mg NA NA NA NA 21% SAE (cholelithiasis/cholecystitis)

Somatostatin Dose Escalation No official dose-finding studies have been performed There may be a value in dose escalation in indolent tumors Those with carcinoid syndrome may also benefit from dose escalation The NETTER-1 trial included a double dose octreotide (60 mg)

CLARINET FORTE Trial Design NETs grade 1 or 2, metastatic or locally advanced unresectable pancreatic or intestinal neuroendocrine tumor progressing on standard dose of lanreotide 120 mg lanreotide every 14 days Primary Endpoint: Median PFS Secondary Endpoints: TTP, OS, ORR, DCR, best overall response, median duration of SD, total number of stools and flushing episodes, change in QOL from baseline, change in tumor biomarker concentrations from baseline US National Institutes of Health. https://clinicaltrials.gov/ct2/show/nct02651987. Accessed November 1, 2016.

RADIANT-2 Study Design Phase III, Double-Blind, Placebo-Controlled Trial Patients with advanced NET and a history of symptoms attributed to carcinoid syndrome, N = 429 R A N D O M I Z E 1:1 Everolimus 10 mg/d + Octreotide LAR 30 mg/28 days n = 216 Crossover Placebo + Octreotide LAR 30 mg/28 days n = 213 Treatment until disease progression Multiphasic CT or MRI performed every 12 weeks Primary endpoint: PFS (RECIST) Enrollment January 2007 - March 2008 Secondary endpoints: Tumor response, OS, biomarkers, safety, PK OS, overall survival; PK, pharmacokinetics Pavel ME, et al. Lancet. 2011;378(9808):2005-2012.

Percentage Event-Free RADIANT-2: PFS by Central Review* 100 80 60 Kaplan-Meier median PFS Everolimus + Octreotide LAR: Placebo + Octreotide LAR: Hazard ratio = 0.77; 95% CI [0.59-1.00] P value =.026 16.4 months 11.3 months 40 20 0 No. of patients still at risk Total events = 223 Censoring times E + O (n/n = 103/216) P + O (n/n = 120/213) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 E + O P + O 216 213 202 202 167 155 129 117 120 106 102 84 81 72 69 65 63 57 * Independent adjudicated central review committee P-value is obtained from the one-sided log rank test Hazard ratio is obtained from unadjusted Cox model Pavel ME, et al. Lancet. 2011;378(9808):2005-2012. Time, Months 56 50 50 42 42 35 33 24 22 18 17 11 11 9 4 3 1 1 1 0 E + O = Everolimus + Octreotide LAR P + O = Placebo + Octreotide LAR 0 0

RADIANT-4: Study Design Patients with advanced, progressive, nonfunctional NET of lung or GI origin (N = 302) Absence of active symptoms or any history of carcinoid syndrome Pathologically confirmed advanced disease Radiologic disease progression in 6 months R A N D O M I Z E 2:1 Everolimus 10 mg/day N = 205 Placebo N = 97 Treated until centrally confirmed PD or intolerable toxicity Endpoints: Primary: PFS (central) Key Secondary: OS Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK Stratified by: Prior SSA treatment (yes vs no) Tumor origin (stratum A vs B)* WHO PS (0 vs 1) *Two strata: Stratum A appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary Stratum B lung, stomach, rectum, and colon except cecum Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary analysis. Yao JC, et al. Lancet. 2016;387(10022):968-977.

Probability of Progression-Free Survival (%) RADIANT-4: Everolimus for Advanced Neuroendocrine Tumors of the Lung or GI Tract: Centrally Confirmed PFS 100 90 80 70 Kaplan-Meier median PFS Everolimus: 11.0 months (95% CI, 9.2-13.3) Placebo: 3.9 months (95% CI, 3.6-7.4) HR = 0.48 (95% CI, 0.35-0.67); P<.00001 60 50 40 30 20 Censoring times 10 Everolimus (n/n = 113/205) Placebo (n/n = 65/97) 0 0 2 4 6 8 10 12 15 18 21 24 27 30 Months Yao JC, et al. Lancet. 2016;387(10022):968-977.

RADIANT-4: Everolimus for Advanced Neuroendocrine Tumors of the Lung or GI-Tract: Investigator-Assessed PFS 90 80 70 60 50 40 30 20 10 0 Probability of Progression-Free Survival, %100 Censoring times Everolimus (n/n = 98/205) Placebo (n/n = 70/97) Kaplan-Meier median PFS Everolimus: 14.0 months (95% CI, 11.24-17.71) Placebo: 5.5 months (95% CI, 3.71-7.39) HR = 0.39 (95% CI, 0.28-0.54); P<.00001 0 2 4 6 8 10 12 15 18 21 24 27 30 No. of patients still at risk Months Everolimus 205 171 148 132 108 93 75 59 33 15 5 0 Placebo 97 70 47 35 27 25 21 19 10 6 4 0 0 0 P value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. Yao JC, et al. Lancet. 2016;387(10022):968-977.

RADIANT-4: PFS HR by Stratification Factors Central Review Subgroups No. Hazard Ratio (95% CI) Prior SSA treatment Yes No Tumor origin* Midgut Non midgut WHO PS 0 1 157 145 153 149 216 86 0.52 (0.34-0.81) 0.60 (0.30-0.94) 0.63 (0.40-1.02) 0.43 (0.28-0.66) 0.58 (0.41-0.84) 0.50 (0.28-0.91) *Based on prognostic level, grouped as: Stratum A (better prognosis) - appendix, cecum, jejunum, ileum, duodenum, and NET of unknown primary) Stratum B (worse prognosis) - lung, stomach, rectum, and colon except cecum) 0.1 0.4 1 10 Everolimus Better Placebo Better Hazard ratio obtained from unstratified Cox model. SSA, somatostatin analogs; WHO PS, World Health Organization performance status Yao JC, et al. Lancet. 2016;387(10022):968-977.

RADIANT-4: Activity in Less Favorable Subgroups Tumor grading Grade 1 Grade 2 Treatment naïve* Yes No Prior chemotherapy Yes No Baseline CgA >2xULN 2xULN Liver Tumor Burden None 10% >10%-25% >25% No. 194 107 117 185 77 225 139 138 48 180 37 35 Hazard Ratio (95% CI) 0.57 (0.39-0.84) 0.49 (0.29-0.83) 0.65 (0.39-1.08) 0.51 (0.35-0.76) 0.35 (0.19-0.64) 0.60 (0.42-0.86) 0.40 (0.25-0.62) 0.70 (0.45-1.11) 0.49 (0.20-1.20) 0.67 (0.45-1.00) 0.62 (0.20-1.93) 0.18 (0.06-0.50) 0.1 0.4 1 10 Yao JC, et al. Lancet. 2016;387(10022):968-977. Everolimus Better Placebo Better

RADIANT-4: Adverse Events Everolimus N = 202 Presented are drug-related adverse events in 15% of patients (safety set) *Includes stomatitis, aphthous stomatitis, mouth ulceration, and tongue ulceration Includes all infections Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis Placebo N = 98 Drug-related adverse events All grades Grade 3/4 All grades Grade 3/4 Stomatitis* 63% 9% 19% 0 Diarrhea 31% 7% 16% 2% Fatigue 31% 3% 24% 1% Infections 29% 7% 4% 0 Rash 27% 1% 8% 0 Peripheral edema 26% 2% 4% 1% Nausea 17% 1% 10% 0 Anemia 16% 4% 2% 1% Decreased appetite 16% 1% 6% 0 Asthenia 16% 1% 5% 0 Noninfectious pneumonitis 16% 1% 1% 0 Dysgeusia 15% 1% 4% 0 Yao JC, et al. Lancet. 2016;387(10022):968-977.

RADIANT-4 QoL: Time to Definitive Deterioration 7 Points on the FACT-G Total Score Pavel M, et al. J Clin Oncol. 2016;34(suppl): Abstract e15657

Midgut NET: NETTER-1 Phase III Study of 177 Lu-Dotatate + Octreotide vs High-Dose Octreotide Treatment and assessments Tumor burden assessment (RECIST criteria) every 12 weeks Dose 1 Dose 2 Dose 3 Dose 4 Midgut NET n = 115 4 administrations of 7.4 GBq of 177 Lu-Dotatate every 8 weeks + octreotide 30 mg Octreoscan positive Progression within 3 years n = 115 Octreotide LAR 60 mg every 4 weeks 5 years of followup Strosberg J et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6.

NETTER-1: PFS N = 229 (ITT) 1.0 Number of events: 90 177 Lu-Dotatate: 23 Octreotide 60 mg LAR: 67 0.8 177 Lu-Dotatate Median PFS: Not reached 0.6 0.4 Octreotide LAR 60 mg Median PFS: 8.4 months 0.2 0 HR 0.209; 95% CI: 0.129-0.338 P<.0001 0 5 10 15 20 25 30 Strosberg J et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6.

NETTER-1: Objective Response Rate 177-Lu-Dotatate (n = 101) Sandostatin LAR 60 mg (n = 100) Complete response (n) 1 0 Partial response (n) 17 3 Objective response rate 18% 3% Confidence interval (95%) 10%-25% 0%-6% Statistical significance P =.0008 All patients (n = 116) (n = 113) Progressive disease 5 (4%) 27 (24%) Stable disease 77 (66%) 70 (62%) Strosberg J et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6.

NETTER-1: Most Common Adverse Events 177 Lu-Dotatate + 30 mg OCT LAR (n = 111) 60 mg OCT LAR (n = 110) All Grades Grade 3-4 All Grades Grade 3-4 Nausea 59% 4% 12% 2% Vomiting 47% 7% 10% 0% Fatigue/asthenia 40% 2% 25% 2% Diarrhea 29% 3% 19% 2% Musculoskeletal pain 29% 2% 20% 1% Abdominal pain 26% 3% 26% 5% Thrombocytopenia 25% 2% 1% 0% Lymphopenia 18% 9% 2% 0% Decreased appetite 18% 0% 8% 3% Strosberg JR, et al. J Clin Oncol. 2016;34(suppl 3): Abstract 194.

Proportion of Patients 1.0 0.8 0.6 Sunitinib Phase III: PFS by Investigator Review Median PFS Sunitinib 11.4 months (95% CI 7.4, 19.8) Placebo 5.5 months (95% CI 3.6, 7.4) HR = 0.42 (95% CI 0.26, 0.66) P<.001 0.4 0.2 0 Number at risk Sunitinib Placebo Events Sunitinib 30/86 Placebo 51/85 0 5 10 15 20 25 Time, Months 86 39 19 4 0 0 85 28 7 2 1 0 Raymond E, et al. N Engl J Med. 2011;364(6):501-513. Blumenthal GM, et al. Oncologist. 2012;17(8):1108-1113.

Phase III Trial: Sunitinib vs Placebo in pnet Event Sunitinib (n = 83) Placebo (n = 82) All grades Grade 1 or 2 Grade 3 or 4 All grades Grade 1 or 2 Grade 3 or 4 Number of patients (%) Diarrhea 49 (59) 45 (54) 4 (5) 32 (39) 30 (37) 2 (2) Nausea 37 (45) 36 (43) 1 (1) 24 (29) 23 (28) 1 (1) Asthenia 28 (34) 24 (29) 4 (5) 22 (27) 19 (23) 3 (4) Vomiting 28 (34) 28 (34) 0 25 (30) 23 (28) 2 (2) Fatigue 27 (32) 23 (28) 4 (5) 22 (27) 15 (18) 7 (8) Hair-color changes 24 (29) 23 (28) 1 (1) 1 (1) 1 (1) 0 Neutropenia 24 (29) 14 (17) 10 (12) 3 (4) 3 (4) 0 Abdominal pain 23 (28) 19 (23) 4 (5) 26 (32) 18 (22) 8 (10) Hypertension 22 (26) 14 (17) 8 (10) 4 (5) 3 (4) 1 (1) Palmar-plantar erythrodysesthesia 19 (23) 14 (17) 5 (6) 2 (2) 2 (2) 0 Anorexia 18 (22) 16 (19) 2 (2) 17 (21) 16 (20) 1 (1) Stomatitis 18 (22) 15 (18) 3 (4) 2 (2) 2 (2) 0 Raymond E, et al. N Engl J Med. 2011;364:501-513.

TELESTAR: Phase III Study Design *Including a blinded titration step of one week of 250 mg TID BM, bowel movement; TID, three times daily Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.

TELESTAR: Inclusion/Exclusion Criteria Key Inclusion Criteria Well-differentiated metastatic NET Documented carcinoid syndrome with 4 BMs/day Currently receiving stable-dose ( 3 months) SSA therapy Minimum SSA dose: Octreotide LAR 30 mg or lanreotide depot 120 mg, every 4 weeks Higher dose/frequency allowed Key Exclusion Criteria >12 BMs/day Evidence of Clostridium difficile or other enteric infection Previous tumor-directed therapy ( 4 weeks prior to screening) History of short bowel syndrome Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.

TELESTAR: Reduction in Daily BM Frequency Averaged Over Double-Blind Treatment Phase Hodges-Lehman estimator of treatment differences estimated a reduction versus placebo of -0.81 BMs daily for telotristat etiprate 250 mg dose (P<.001) -0.69 for telotristat etiprate 500 mg dose (P<.001) Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.

TELESTAR: Reduction in Mean Daily BM Frequency at Baseline and Week 12 All patients continue SSA therapy throughout study period. Data included only patients for whom both baseline and week 12 assessments were available. Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.

TELESTAR: Mean Absolute Change in Urinary 5-HIAA (mg/24 h) From Baseline to Week 12 All patients continue SSA therapy throughout study period. Data included only patients for whom both baseline and week 12 assessments were available. Wilcoxon rank-sum test showed significant differences for each telotristat etiprate dose vs placebo (P<.001) Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.

TELESTAR: Adverse Events (AEs) of Interest Category, n (%) Placebo a (n = 45) Telotristat Etiprate a 250 mg (n = 45) Telotristat Etiprate a 50 mg (n = 45) Total Nausea 5 (11.1) 6 (13.3) 13 (28.9) 24 (17.8) Severe nausea 1 (2.2) 1 (2.2) 0 2 (1.5) Discontinuation due to nausea 1 (2.2) 0 0 1 (0.7) Depression 3 (6.7) 1 (2.2) 6 (17.7)) 10 (7.4) Depressed mood 0 1 (2.2) 2 (4.4) 3 (2.2) Severe depression or depressed mood Discontinuation due to depression or depressed mood 0 0 0 0 0 0 0 0 a All patients continue SSA therapy throughout study period Events of depression and nausea were mild or moderate and did not lead to treatment discontinuation Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.

TELECAST: A Phase III Companion Trial to TELESTAR N = 76 Treated with SSA with <4 BM/day or not treated with SSA R A N D O M I Z E 250 mg telotristat etiprate TID (n = 25) 500 mg telotristat etiprate TID (n = 25) Placebo TID (n = 26) Primary endpoint: Safety and percentage change from baseline in urinary 5- HIAA Secondary endpoint: change from baseline in number of bowel movements, stool consistency, number of cutaneous flushing episodes, abdominal pain, and change in the frequency of rescue short-acting, somatostatin analog used to treat carcinoid syndrome symptoms Pavel M, et al. Presented at: North American Neuroendocrine Tumor Society (NANETS); October 1, 2016; Jackson, Wyoming. Abstract C8.

TELECAST Results Placebo Treatment description Placebo Telotristat etiprate 250 mg P value vs Placebo Treatment Telotristat etiprate 500 mg P value vs Placebo Number of patients 26 25 25 Number of evaluable patients N/A N/A N/A Placebo-adjusted change in urinary 5-HIAA from baseline to week 12 (Endpoint = primary) N/A -54.0% (P<.001) -89.7% (P<.001) Placebo-adjusted change in daily BM frequency from baseline to week 12 (Endpoint = secondary) N/A -0.45 events/day (P =.004) -0.54 events/day (P<.001) 30% reduction in BM frequency for at least 50% of the days (Endpoint = secondary) 0% 40% (P =.001) 40% (P =.001) Pavel M, et al. Presented at: North American Neuroendocrine Tumor Society (NANETS); October 1, 2016; Jackson, Wyoming. Abstract C8.

Treatment Landscape for Advanced NETs 2016 Site Octreotide Lanreotide 177 Lu- DOTATATE Streptozocin Sunitinib Everolimus Disease status Treatment naïve Stable Progressive over 3 years Historical Progressive over 12 months Progressive over 6 months* Lung RADIANT-4 Stomach CLARINET RADIANT-4 Duodenum CLARINET RADIANT-4 Pancreas CLARINET Historical Phase III RADIANT-3* Small bowel Appendix PROMID CLARINET NETTER-1 RADIANT-4 Colon CLARINET RADIANT-4 Rectum CLARINET RADIANT-4 Unknown 1 RADIANT-4 *RADIANT-3 requires documentation of progressive disease (PD) in the prior 12 months. RADIANT-4 requires documentation of PD during prior 6 months. Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663. Caplin ME, et al. N Engl J Med. 2014;371(3):224-233. Strosberg J, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6. Raymond E, et al. N Engl J Med. 2011;364(6):501-513. Yao JC, et al. J Clin Oncol. 2008;26(26):4311-4318. Yao JC, et al. N Engl J Med. 364(6):514-523. Yao JC, et al. Lancet. 2016;387(10022):968-977.

GEP NETs represent a heterogeneous disease with multiple facets and increasing incidence; typical features include high somatostatin receptor expression and relatively slow growth Careful consideration of primary site, disease extent, histology (grade/ki67), symptoms, performance status, and functional imaging findings needed to optimize treatment decisions at each point in the disease Somatostatin analogs are the backbone of systemic treatments Effective second-line and further line antiproliferative treatments include everolimus, sunitinib, PRRT and telotistat etiprate (if approved) for symptom control of carcinoid syndrome