What Do We Still Need to Know? New Frontiers and Treatment Advances for Metastatic Enteropancreatic Neuroendocrine Tumors What Do We Know? What Do We Still Need to Know? The Rapidly Evolving Landscape of Therapeutic Options and Patient Selection Strategies for GEP-NETs— A Year 2015 Status Report for the GI Cancer Specialist

GEP-NET Overview Annual incidence of NET is 5.25 cases per 100,000 Americans (SEER Database)1 Incidence has increased by 500% in the past 30 years – more than other cancers. Today, NET is the most prevalent GI malignancy after colon cancer, affecting over 100,000 Americans. 3X more prevalent than pancreatic adenocarcinoma 2X more prevalent than stomach adenocarcinoma 1. Modlin IM, Latich I, Zikusoka M, Kidd M, Eick G, Chan AK. J Clin Gastroenterol. 2006;40(7):572-582. 2. Yao JC, Hassan M, Phan A, et al, J Clin Oncol. 2008;26:3063-3072 3. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663

GEP-NET Overview NET is usually metastatic at diagnosis, and 65% will die in the first 5 years after diagnosis (SEER data). Conventional chemotherapy has limited efficacy. Lanreotide is approved therapy for GEP-NETs including carcinoids. For NET of pancreatic origin, streptozocin, sunitinib, everolimus, and lanreotide have all been approved. Octreotide LAR is approved as a symptom control medication (flushing and diarrhea in carcinoid, diarrhea in VIPoma syndrome.1 There remains a significant unmet need for effective and safe therapies in patients with metastatic NET. 1. Modlin IM, Latich I, Zikusoka M, Kidd M, Eick G, Chan AK. J Clin Gastroenterol. 2006;40(7):572-582. 2. Yao JC, Hassan M, Phan A, et al, J Clin Oncol. 2008;26:3063-3072 3. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663

Carcinoid – Neuroendocrine Tumor Program Multidisciplinary Management Team Medical Oncology Endocrinology Radiation Cardiology Gastro- enterology Pathology Interventional Radiology Diagnostic Nuclear Medicine Surgery PATIENT

Perspectives on Chemotherapy for GEP-NET Chemotherapy for NET usually has a lower objective response rate than for most solid tumors. Pancreatic NET (pNET) is the exception. Despite the low response rate, progression-free survival can be prolonged with appropriate chemotherapy, and quality of life can be improved. More metabolically active NETs (high Ki-67, high SUV on FDG-PET) are more likely to respond to chemotherapy by tumor shrinkage.

Perspectives on Chemotherapy for GEP-NET 2 GEP-NETs are very vascular and cells express VEGF and other pro-angiogenic targets. Growth factor receptors and their downstream effectors are prominently expressed, inviting new targets such as c-KIT, EGFR, IGF-1R, phosphoinositide-3-kinase, AKT, mTOR, and PDGF. Optimal integration of new systemic therapies with local and regional cytoreductive techniques, and PRRT remains a challenge. Optimal sequencing of the multiple active agents in pancreatic NET remains a challenge.

Approved Systemic Therapy for Pancreatic NET Streptozocin Everolimus Sunitinib Lanreotide

Streptozocin Chemotherapy for Pancreatic NET: Overview and Status Streptozotocin + doxorubicin + 5-FU in pancreatic NET: 39% PR by RECIST. Median response duration was 9.3 months. Nephrotoxicity can compromise future PRRT. Kouvaraki, MA et al, J Clin Oncol 2004 Dec 1;22(23):4762-71

Everolimus in Pancreatic NET: RADIANT-3 Trial Progression-free Survival* Kaplan-Meier medians PFS Everolimus: 11.4 months Placebo: 5.4 months Hazard ratio = 0.34; 95% CI [0.26-0.44] P-value: <0.0001 100 80 60 Percentage event-free 40 20 Censoring Times Everolimus (n/N = 95/207) Placebo (n/N = 142/203) 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (months) No. of patients still at risk Everolimus Placebo 207 203 187 180 152 99 126 60 117 52 81 22 49 12 36 5 27 3 22 1 10 1 6 1 2 * Independent adjudicated central review committee P-value obtained from stratified one-sided log rank test Hazard ratio is obtained from stratified unadjusted Cox model

Sunitinib – Phase 3 Trial in Pancreatic NET Pancreatic NETs which had progressed in the last 12 months were randomized to either sunitinib or placebo plus(n=79). Average time to progression was 11.1 months with sunitinib vs. 5.5 months with placebo (hazard ratio 0.397, p<0.001). Significant side effects included low white blood count hypertension, abdominal pain, diarrhea, low blood sugar and hand-foot syndrome (less than 10% of patients). Common mild side effects included mild fatigue, nausea, altered taste, tongue tenderness N Engl J Med Volume s364(6):501-513 February 10, 2011

Lanreotide Autogel Newly Approved for Treatment of GEP-NETs A novel somatostatin analog with high affinity binding to SSTR2. After subcutaneous injection, self-assembly reverses, releasing lanreotide, with 80-85% of drug released by 80 days. Suitable for giving higher and potentially more effective doses in a small volume. Better tolerated by thin or cachectic individuals than I.M. injections Clinical trials of lanreotide autogel have led to recent FDA approval and will be discussed in detail in this meeting.

CLARINET: Primary Endpoint Prespecified PFS Subanalyses – Tumor Location Midgut NETs (n=73) Lanreotide 120 mg vs. PBO HR=0.35 [95% CI: 0.16, 0.80] Pancreatic NETs (n=91) Lanreotide 120 mg vs. PBO HR=0.58 [95% CI: 0.32, 1.04] 3 6 9 12 18 24 27 10 20 30 40 50 60 70 80 90 100 Patients alive and with no progression (%) Time (months) 10 20 30 40 50 60 70 80 90 100 Time (months) Lanreotide 8 events / 33 patients Median PFS not reached Lanreotide 18 events / 42 patients Median PFS not reached Placebo 21 events / 40 patients Median PFS = 21.1 months [95% CI: 17.0, NC] Placebo 31 events / 49 patients Median PFS = 12.1 months [95% CI: 9.4, 18.3] 3 6 9 12 18 24 27 33 32 30 28 24 40 39 36 20 16 Numbers of patients at risk of death or PD 13 42 39 32 29 24 20 49 48 38 33 23 17 13 Numbers of patients at risk of death or PD 8 HR derived from Cox proportional hazards model. CI, confidence interval; HR, hazard ratio; NETs, neuroendocrine tumors; PBO, placebo; PD, progressive disease; PFS, progression-free survival; PNETs, pancreatic neuroendocrine tumors. Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.

Approved Systemic Therapy for Carcinoid Tumors Octreotide and octreotide LAR are approved for the treatment of flushing and diarrhea from carcinoid syndrome. Lanreotide Autogel approved as an antineoplastic for treatment of GEP-NETS, including carcinoid tumors.

New Directions and Clinical Challenges for Treatment and Sequencing Therapy for NET How should the sequence of systemic therapies in NET management be optimized? Based on what evidence? How should local/regional therapy be integrated with systemic therapy? Patient selection? Clinical profiles? Now that lanreotide is approved, when should it be started, and how should it be incorporated into the therapeutic plan of patients with GEP-NETs? What is the roadmap? How should peptide receptor radiotherapy (PRRT) be incorporated into NET management? How should advances in molecular biology/genomics inform treatment decisions? What ongoing large clinical trials are likely to influence therapy in the near future?