PANCREATIC NEUROENDOCRINE TUMORS DECEMBER 12, 2017 IF YOU EXPERIENCE TECHNICAL DIFFICULTY DURING THE PRESENTATION:

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1 PANCREATIC NEUROENDOCRINE TUMORS DECEMBER 12, 2017 IF YOU EXPERIENCE TECHNICAL DIFFICULTY DURING THE PRESENTATION: CONTACT WEBEX TECHNICAL SUPPORT DIRECTLY AT: US TOLL FREE: TOLL ONLY: OR SUBMIT A QUESTION TO THE EVENT PRODUCER VIA THE Q&A PANEL Pancreatic Neuroendocrine Tumors Daniel M. Halperin, MD Assistant Professor Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center 1

2 Disclosures Consultant for Novartis, AbbVie. Research funded by Ipsen, Genentech, Novartis, Tarveda, Dicerna (prior). I will discuss off-label and/or investigational use. Disclosures (cont.) No webinar is a substitute for a personal consultation with a trusted physician. 2

3 Overview Basics of the pancreas and pancreatic neuroendocrine neoplasms (NENs) Epidemiology Clinical presentations Basic biology Modern treatment approaches Future investigational directions This is not conventional pancreas cancer 3

4 Pancreas Anatomy/Physiology 101 Exocrine Acinar cells produce digestive enzymes, delivered to the GI tract by ducts. Endocrine Islet cells secrete hormones into blood. Bardeesy and DePinho, Nat Rev Cancer Dec;2(12): Rising Incidence of Pancreatic NETs Pancreatic Adenocarcinoma 12.5/100,000 Dasari et al., JAMA Oncol Oct 1;3(10):

5 Rising Prevalence of Pancreatic NETs Dasari et al., JAMA Oncol Oct 1;3(10): NET Framework NETs arise from endocrine cells distributed throughout the aerodigestive tract, including the pancreas. Classified in four dimensions: Primary Site Grade Stage Functional Status (hormonal secretion) Histology of adenocarcinoma Hruban and Fukushima, Modern Pathology (2007) 20, S61 S70. Frequently express somatostatin receptors Histology of NET. A: H&E; B: CgA Halperin and Yao, MD Anderson Manual of Medical Oncology, 3e. 5

6 Grading NENs (2017) Grade 1 NET < 2 mitoses/10 HPF, Ki-67 <3% 2 NET 2-20 mitoses/10 HPF, Ki % 3 NET Well-differentiated >20 mitoses/10 HPF, Ki-67 >20% 3 NEC Poorly-differentiated >20 mitoses/10 HPF, Ki-67 >20% Grade is dependent on appearance and rate of cellular division Grade, Stage, Primary Site Grade 1-2 Grade 3 Metastatic Grade 1-2 NET Primary Tumor Site Appendix NA Cecum 98 Colon 14 Lung 24 Pancreas 60 Rectum 33 Small Intestine 103 Stomach 29 Median Survival (months) Yao et al., J Clin Oncol 2008; 26:3063 Dasari et al., JAMA Oncol Oct 1;3(10):

7 Functional Status Gastrinoma (gastrin) Glucagonoma (glucagon) Insulinoma (insulin) VIPoma (vasoactive intestinal peptide) Reflux Diabetes Low blood sugar Dementia Confusion Ulcers Dermatitis Improvement with eating Diarrhea Diarrhea DVT Weight gain Adapted with permission from James Yao Non-functional Presentations Completely incidental Symptoms from primary tumor Painless jaundice from pancreatic head tumor obstructing biliary drainage Bleeding gastric varices from pancreatic tail tumor occluding splenic vein Symptoms from metastatic disease Right upper quadrant pain from liver metastases 7

8 Genetics/Genomics Most pancreatic NETs are not inherited or associated with a familial syndrome MEN1 DAXX/ATRX TSC2, NF1 VHL BRCA2 Scarpa et al., Nature 2017; 543:65 Alternative Lengthening of Telomeres in pnet Loss of DAXX or ATRX results in telomerase-independent elongation of telomeres, conferring cellular immortality. Heaphy et al., Science

9 Chromosomal instability in pancreatic NETs Yao et al, J Clin Oncol 34, 2016 (suppl; abstr e23284) Summary Pancreatic NETs arise from endocrine islet cells. NET grade, stage, and primary site all contribute to clinical course and treatment options. Pancreatic NETs can cause dramatic syndromes of hormone hypersecretion. But they usually do not. New data are accumulating regarding the mutations that tend to be present in pancreatic NETs. Most pancreatic NETs are not part of a familial/inherited syndrome. 9

10 Management Management Principles Removal of localized and limited metastatic disease Advanced disease Control of hormone secretion Control of tumor growth Minimize toxicity 10

11 Cut when you can (should?) Surgical series suggest overall survival is better in patients undergoing surgery. Surgery appears to have survival advantage over observation or HAE. However, while almost anything can be cut out, the question is frequently whether it should. Bacchetti et al., Int J Hepatol 2013: Does everyone need active therapy?

12 Lanreotide in GEP-NET CLARINET Lanreotide: a somatostatin analogue binding SSTRs 2,5. Patients with SSA-avid GEP-NETs, Ki67 < 10%. Lanreotide vs. placebo. D- phe cys phe D- phe cys tyr S D- trp S D- trp S lys S lys Octreotide cys thr throl thr- NH 2 cys val Lanreotide Caplin et al., N Engl J Med 2014;371:224 Lanreotide toxicities Characteristic toxicities: Diarrhea (steatorrhea) Flatulence Cholelithiasis Hyperglycemia 12

13 Streptozocin in pnet Streptozocin: islet-specific alkylator. Initially tested in 4 pnet and 4 carcinoid patients at NCI. 1 CR for 1 year in pnet patient. 3 subsequent prospective randomized studies confirmed efficacy. However, radiographic response rates with doublets were < 10 %. The triplet of FAS has been reported to yield a response rate of 40%. Characteristic toxicities include neutropenia, hair loss, nausea/vomiting, possible cardiac toxicity mos 2.2 vs 1.5 yrs p<0.004 Moertel et al., N Engl J Med 1980; 303:1189 Moertel et al., N Engl J Med 1992; 326:519 Temozolomide Widely used but off-label (not FDA approved for NET) Range of response rates reported, probably approaching 30-40% Prospective randomized study of temozolomide +/- capecitabine is ongoing Characteristic toxicities include unusual infections, nausea, thrombocytopenia Strosberg et al., Cancer

14 Everolimus in pnet RADIANT-3 Everolimus: PO mtor inhibitor. Patients with G1-2 advanced pnets, PD within 12 months. Everolimus vs. placebo. Yao et al., N Engl J Med 2011;364:514 Everolimus toxicities Characteristic toxicities: Stomatitis Rash (capelike) Pneumonitis Lymphopenia and infections Hyperglycemia 14

15 Sunitinib in pnet Sunitinib: PO VEGFR inhibitor Patients with G1-2 advanced pnets, PD within 12 months. Sunitinib vs. placebo. Raymond et al., N Engl J Med 2011;364:501 Sunitinib toxicities Characteristic toxicities: Diarrhea Hair color changes Hypertension PPEDE 15

16 Study Liver-directed treatment options Patients n Device used Toxicity ORR (RECIST 1.0) Kennedy et al. 148 Yttrium-90(resin) 33% (grade III), fatigue (6.5%) King et al. 58 Yttrium-90(resin) plus 5-FU Radiation gastritis (2 pts), duodenal ulcer (1 pts) 63% Median: 70m 39% Median: 36m Survival times and rates Cao et al. 58 Yttrium-90(resin) Not reported 39.2% Median: 36m plus 5-FU Memon et al. 40 Yttrium-90(glass) Fatigue (63%,), nausea/vomiting (40%), grade III, IV(bilirubin, 8%; albumin, 2%; lymphocyte, 38%) WHO: 64.0%; EASL: 71.4% Median: 34.4m Loewe et al. 23 HAE Not reported 73% Median: 69m; Gupta et al 49 HAE (42) vs TACE (27) Overall complications: TACE, 20%; bland, 12% [HRS, Sepsis, abscess] Dong & Carr 123 TACE Abdominal pain (44%), diarrhoea (30%), weight loss (22%) HAE: 25% TACE: 50% 62% Mean: 3.3y Median NET: TACE, 33.8m; HAE, 33.2m; pnet: TACE, 31.5m; HAE, 18.2m Kennedy et al., HPB 2015 The Systemic Therapy Ladder Chemotherapy (Streptozocin, Temozolomide) Response Rate Targeted therapies (Everolimus, Sunitinib) Somatostatin Analogues (Octreotide/Lanreotide) Observation Tolerability 16

17 Therapeutic Approach High Volume Consider Cytotoxic Liver-directed Therapy Unresectable pnet Indolent Observation SSA Low Volume Progressive Everolimus Sunitinib Have we moved the needle? (All grades) Metastatic/Distant Grade 1-2 NET Primary Tumor Site Appendix NA Cecum 98 Colon 14 Lung 24 Pancreas 60 Rectum 33 Small Intestine 103 Stomach 29 Median Survival (months) Yao et al., J Clin Oncol 2008; 26:3063 Dasari et al., JAMA Oncol Oct 1;3(10):

18 Investigational Strategies Chemotherapy Temozolomide +/- capecitabine (NCT ) Molecularly-targeted therapy Everolimus + ribociclib (NCT ) Cabozantinib Immunotherapy PDR001 (NCT ) Atezolizumab + bevacizumab (NCT ) Receptor-targeted therapy 177 Lu-DOTATATE 177 Lu-DOTA-JR11 (NCT ) PEN-221 (NCT ) Cabozantinib (phase II) 30 Carcinoid 30 pnet Prior everolimus and/or sunitinib Courtesy of Jennifer A. Chan, MD; GI ASCO

19 Pembrolizumab in PD-L1+ NET 25% pnet PD-L1+ Mehnert et al., ESMO 2017 PRRT in midgut NET NETTER Lu-DOTA-Octreotate (DOTATATE): a radioactive isotope conjugated to somatostatin analogue. Patients with G1-2 midgut NET, PD on octreotide LAR 30, somatostatinavid. DOTATATE vs. octreotide LAR 60mg. Toxicity profile includes myelosuppression, nausea. PFS HR [95% CI ]; P< Strosberg et al., NEJM 2017; 376:

20 Symptomatic Control pnet Syndromes and Medical Management Tumor Signs/Symptoms Medical Management Insulinoma Gastrinoma Glucagonoma VIPoma Hypoglycemia with confusion, diaphoresis, weakness Refractory PUD, diarrhea Rash (necrotizing migratory erythema), diabetes, DVT Profound secretory diarrhea, electrolyte dyscrasias Frequent small meals, dextrose, diazoxide, everolimus PPI, SSA SSA SSA Adapted with permission from Halperin, Kulke, Yao. Annu Rev Med 2015; 66:1 20

21 Octreotide Octreotide LAR is FDA approved for control of carcinoid syndrome (20mg) and VIPoma. Agonist of SSTRs 2, 5. Rubin et al., JCO 1999 Kvols et al., NEJM 1986 Liver-directed therapy for hormone reduction Mitty et al., Radiology

22 Surgical Debulking R1 or R0 resection of liver metastases +/- primary tumor and nodal metastases Wilson and Butterick. Ann Surg 1959 Osborne et al., Ann Surg Onc 2006 Investigational: PRRT 177 Lutitium conjugated to octreotate for receptor-targeted tumor irradiation. Global Health Status Diarrhea Pain Flushing 177 Lu arm average % of patients Improvement 28%** 15% Worsening 18% 26% Improvement 39%** 23% Worsening 19% 23% Improvement 41% 28% Worsening 17% 25% Improvement 42% 38% Worsening 22% 19% 60mg Oct arm average % of patients Strosberg et al., J Nucl Med May 1, 2017 vol. 58 no. supplement Khan et al., J Nuc Med

23 Grade 3 NEC is not NET Grading NENs (2017) Grade 1 < 2 mitoses/10 HPF, Ki-67 <3% mitoses/10 HPF, Ki % 3 NET Well-differentiated >20 mitoses/10 HPF, Ki-67 >20% 3 NEC Poorly-differentiated >20 mitoses/10 HPF, Ki-67 >20% Grade is dependent on appearance and rate of cellular division 23

24 Grade 3 NEN Genomics Gene SCLC (N = 593) Pancreas (N = 123) Colon (N = 92) Other GI (N = 59) TP53 90% P,C,O 18% S,C,O 59% S,P 49% S,P RB1 67% P,C,O 10% S,C,O 34% S,P 29% S,P CDKN2A 3% P,O 21% S,C 5% P,O 25% S,C MEN1 1% P 33% S,C,O 3% P 2% P CDKN2B 1% P,O 16% S,C 1% P,O 19% S,C DAXX 0% P 20% S,C,O 0% P 0% P APC 2% C 3% C 47% S,P,O 8% C KRAS 4% C 7% C 37% S,P,O 3% C CCNE1 4% O 2% O 1% O 17% S,P,C S, P, C or O : Statistically significant difference compared to S = SCLC, P = Pancreas, C = colon, O = Other GI Bergsland et al., GI ASCO 2016 Grade 3 NEC has a distinct natural history Grade 1-2 Grade 3 Yao et al., J Clin Oncol 2008; 26:

25 Cisplatin/Etoposide for Grade 3 NEC Mitry et al., Br J Cancer (1999) 81(8), Investigational Strategies Chemotherapy FOLFIRINOX (NCT ) EP vs. CAPTEM (NCT ) Immunotherapy PDR001 (NCT ) Pembrolizumab (NCT ) Avelumab (NCT ) Receptor-targeted therapy PEN-221 (NCT ) Rova-T (NCT ) 25

26 Take Home Points Pancreatic NETs are not conventional pancreas cancer (adenocarcinoma) Pancreatic NECs are not conventional pancreatic NETs. Pancreatic NETs are increasing in incidence. Patients are living longer than ever. Much progress has been made in developing new effective therapy. Current challenges include: Choosing from the standard therapy menu. Choosing from the investigational menu. Thank you for your participation. If you have questions, please contact Patient Central at PANCAN or 26