New Developments in the Care and Management of Patients with Gastroenteropancreatic Neuroendocrine Tumors Dr. Tim Asmis The Ottawa Hospital Cancer

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1 New Developments in the Care and Management of Patients with Gastroenteropancreatic Neuroendocrine Tumors Dr. Tim Asmis The Ottawa Hospital Cancer Centre MD, FRCPC CAGPO September 2018

2 Disclosures Consultant : Ipsen, Novartis Fellowship funding : Novartis

3 Objectives NET Review the updated terminology and classification for NET Provide an overview of presentation and diagnostic work up of NET Discuss treatment options & their availability, as well as management of symptoms and complications of NET - Review response rates - Discuss the most common toxicities from treatment & their management

4 Progress in the Land of Neuroendocrine Classification/Guidelines Karzinoide coined by Oberndofer WHO classification Carcinoids WHO classification NET and NEC 6 AJCC/UICC TNM classification GI/pNET /08 ENETS guidelines 4 ; TNM staging 5, NANETS guidelines ESMO guidelines 22, /16 ENETS guidelines including TC/AC WHO classification Lung NET/carcinoids Treatments 1982 STZ pnet /89 OCT SC CS 25, STZ combination: survival benefit pnet LAN symptom control 24 OCT LAR carcinoid tumors 23,26, / PROMID OCT LAR: antitumor activity 9,31 RADIANT-3 EVE in pnet 11,12,32,33 Sunitinib phase 3 pnet 13,31, /15 CLARINET LAN GEP NET 16,17,29 ELECT LAN: symptom control /16 RADIANT-4 EVE NF GI and lung NET 15, TELESTAR telotristat etiprate CS 20 NDA filed 3/30/16 US Approval US/EU Approval EU Approval RADIANT-2 EVE + OCT LAR in mnet w/cs 14 NETTER 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; LAN, lanreotide; LAR, long-acting repeatable; m, metastatic; NANETS, North American Neuroendocrine Tumor Society; NDA, New Drug Application; NEC, neuroendocrine carcinomas; NET, neuroendocrine tumors; NF, nonfunctional; OCT, octreotide; pnet, pancreatic NET; SC, subcutaneous; STZ, streptozocin; TC, typical carcinoid; UICC, Union for International Cancer Control; WHO, World Health Organization. For distribution in response to an unsolicited request for medical information subject to local NP4 approval.

5 Canadian Consensus Recommendations PNET: November 2014

6 Canadian Consensus Recommendations GI: 2010-> Update 2016

7 Mentors Thanks to my mentors Takes TEAM Surgery, pathology, radiation oncology, nuclear medicine, cardiology, nurses, allied health professionals Pharmacy Drug navigators

8 Case DG 49 year old female, with hypertension Two year history of diarrhea and flushing Diarrhea, about 8-10 per day Abdominal pain Facial flushing (especially with certain foods and intraabdominal pressure) Exam: Obvious flushing: pinkish and hot face and upper chest Chest clear, Heart sounds normal Abdomen: fullness and palpable liver 2 cm below costophrenic angle

9 Case DG Went to an allergist about diarrhea, felt it was food intolerance Ordered urine 5HIAA= 800. Normal <50 mmol/day WHAT Clinical SYNDROME IS THIS? What percentage of patients have symptomatic NETs?

10 Neuroendocrine Tumour Classification: Functioning Neuroendocrine Tumours Gastrointestinal Pancreatic FUNCTIONING Non-functioning Functioning Non-functioning 40% 60% 30% 70% FUNCTIONING = Hormone secretion that results in a clinical syndrome Serotonin secreting tumour = CARCINOID SYNDROME Insulin-producing pancreatic NET causing episode hypoglycemia = INSULINOMA Gastrin producing tumor with Zollinger-Ellison syndrome = GASTRINOMA

11 NET Biomarkers - Urinary 5- Hydroxyindoleacetic Acid (5-HIAA) Measured in a 24-hour urine specimen High levels have prognostic value and can be associated with Reduced survival Progressive carcinoid heart disease Tryptophan 5-Hydroxytryptophan Serotonin Serotonin stored in secretory granules Serotonin in blood 5-Hydroxyindoleacetic acid (5HIAA) in urine Adapted from : 1.Kocha W, et al. Curr Oncol. 2010;17(3): Feldman JM. Clin Chem. 1986;32(5): Formica V, et al. Br J Cancer. 2007;96(8): de Herder WW. Best Pract Res Clin Endocrin Metab. 2007;212(1): Goldfinger SE et al: Clinical features of the carcinoid syndrome Last updated: September 2014.

12 Case DG Given her carcinoid syndrome Where do we suspect the primary site of disease? Do we think she will have metastatic disease?

13 *There are many other hormones, syndromes and symptoms that can be caused by NETs. These are some of the most common. Adapted from Modlin IM, et al. Lancet Oncol. 2008;9(1):61-72; Kaltsas GA, et al. Endocr Rev. 2004;25(3): ; and Barakat MT, et al. Endocr Relat Cancer. 2004;11(1):1-18. Syndromes with Nonspecific Symptoms Caused by Hormones and Peptides Secreted by Functional NETs* NET Location Small bowel Pancreas Approx. 2/3 of NETs are Functional 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

14 CASE 49 year old female with Carcinoid Syndrome and high Urine 5HIAA What other tests do you want to order? What systemic treatment do we want to initiate?

15 Case DG CT scan Chest/Abdomen/Pelvis: 2.7cm lesion in small bowel mesentery + multiple hypodense lesions + query omental disease Biopsy of liver: Well differentiated NET, Ki67 2% Octreotide scan: strong uptake in liver plus mesenteric lymph nodes near ileum Chromagranin = 400 (normal <110ng/ml)

16 What about 68Ga-Dotatate PET Prospective study 138 GEP NETs Any patient with suspected NET on imaging % lesions detected Other findings 68Ga PET 95.1 % -Found 4/14 UN Primary - 33% patient had change in management - HIGH Sensitivity 93% - HIGH Specificity 95% - Caution in Insulinomas Anatomic imaging Multiphasic CT MRI 45.3% 111In-pentetreotide SPECT/CT 30.9% Sadowski JCO Feb 2016, Treglia Enodocrine 2012

17 WHO 2010 Classification 1,2 Good Prognosis of patients with NETs Poor The proliferative rate can be assessed by: Mitotic rate: number of mitoses per unit area of tumor (mitoses/10 HPFs or mitoses/2 mm 2 ) Ki-67 index: percentage of cells that stain positive for the proliferation marker Ki-67 WHO, World Health Organization; NETs, neuroendocrine tumors; HPF, high power field. 1. Klimstra DS, et al. Pancreas. 2010;39(6): Lawrence B, et al. Endocrinol Metab Clin North Am. 2011;40(1):1-18.

18 WHO 2017 Grading System Neuroendocrine Neoplasm NENs Well differentiated NENs Ki67 (%) Mitotic Index (mitosis 10/ HPF) Neuroendocrine tumour (NET) G1 <3 <2/10 Neuroendocrine tumour (NET) G /10 Neuroendocrine tumour (NET) G3 >20 >20 Poorly differentiated NENs Neuroendocrine carcinoma (NEC) G3 >20 >20 Mixed neuroendocrinenonneuroendocrine neoplasm (MiNEN) Well Differentiated NECs are in general unresponsive to Platinum based chemotherapy (Sorbye, NORDIC data, Ann Oncology 2013)

19 NET Biomarkers - Chromogranin A (CgA) CgA levels are elevated in % of patients with welldifferentiated NETs In classical midgut NETs, CgA levels are elevated to times above the norm Different assays and thresholds are used Adapted from : 1. Öberg K, et al. Ann Oncol. 2004;15(6): Jensen TB, et al. Clin Chem. 1999;45(4): Nehar D, et al. Clin Endocrinol (Oxf). 2004;60(5): Bajetta E, et al. Cancer. 199;86:

20 Sensitivity and Specificity of The Two Key Biochemical Tests for Well-Differentiated Gastroenterohepatic NETs Test Sensitivity Specificity (True +ve) (True -ve) Serum chromogranin A (CgA) 62.9% 98.4% Urinary 5-HIAA 73% 100% Key Message: An elevated CgA is not equal to a NET diagnosis. 5-HIAA: 5-hydroxyindoleacetic acid Adapted from Kocha W, et al. Curr Oncol. 2010;17(3):49-64.

21 False-positive Elevations of CgA Can be Due to a Broad Range of Other Factors Other Causes of CgA Elevation Other malignancies Systemic inflammatory diseases Gastrointestinal disorders Endocrine disease Cardiovascular disease Renal disorder Drugs Examples Hepatocellular carcinoma, pancreatic adenocarcinoma, breast, colon, ovarian or prostate cancer Rheumatoid arthritis, systemic inflammatory response syndrome, giant cell arthritis, COPD Chronic atrophic gastritis, pancreatitis, IBD, IBS, liver cirrhosis, chronic hepatitis Hyperparathyroidism, hyperthyroidism Hypertension, cardiac insufficiency, acute coronary syndrome Renal insufficiency Proton pump inhibitors, H 2 -receptor antagonists, glucocorticoids COPD: chronic obstructive pulmonary disease; IBD: inflammatory bowel disease; IBS: irritable bowel syndrome Adapted from Singh S, et al. Expert Rev Gastroenterol Hepatol. 2012; 6(3):

22 CASE Patient is still having crampy abdomen pain: booked for small bowel resection in 3 weeks What to do to avoid a crisis for this patient? Why surgery for this patient?

23 Current Tools for Metastatic NET Targeted Therapy Everolimus Sunitinib Somatostatin analogues Radiolabel Therapy Surgery Resection of Primary Metastatectomy Liver Directed Therapy Chemoembolization Bland Embolization Yttrium 90

24 Why Surgery for metastatic patient? Debulking Surgery Improves QOL with symptom control If primary site is causing symptoms or potential to cause symptoms (intermittent bowel obstruction) will consider resection May also do cholecystectomy at time Retrospective analysis shows improved OS when primary removed HR 0.16 (95% CI ) (Rinke JCO 2009; 27: 4656) Potentially curable resection

25 Case DG ECHO: normal WHY DID WE ORDER THIS? Started Octreotide LAR to improve symptoms also pre-op assessment by anesthesia What dose would you start with?

26 Canadian Consensus SSA doses for symptoms Starting dose Octreotide LAR mg im q 4 wks Lanreotide 120 mg deep sc,q 4 wks Titrate to Octreotide: 60 mg q 2-4 weeks Lanreotide 180 mg q 3 weeks Short acting Octreotide: mcg sc TID Telotristat etiprate (thyrosine hydroxylase inhibitor, for diarrhea, approval pending) Interferon alpha 3-5 million units sc 3x/week Cytoreduction of dominant liver disease Hepatic arterial therapy

27 Symptom control Canadian consensus guideline Refractory diarrhea, rule out other causes Bile salt or fat malabsorption Intestinal hypermobility Short bowel syndrome TELESTAR (ESMO 2015, still waiting Health Canada approval) Telotristat Etiprate: Tryptophan Hydroxylase inhibitor Inhibits enzyme triggers excess serotonin production in NET cell A significant reduction in bowel frequency compared to Placebo 250 mg ORAL TID ò29% 500 mg ORAL TID ò35%

28 Eligible patients were 18 years of age Telotristat Ethyl Xermelo TELESTAR Study had histopathologically confirmed, well-differentiated metastatic NETs, history of carcinoid syndrome were experiencing an average of four or more BMs per day, and were receiving stable-dose SSAs (long-acting release [LAR], depot, or infusion pump) for 3 months before enrollment. 135 Patients were randomly assigned 1:1:1 to receive oral doses, three times per day for 12 weeks, of telotristat ethyl 250 mg, telotristat ethyl 500 mg, or placebo. J Clin Oncol. 2017;35(1):14 23.

29 Telotristat ethyl (Xermelo) Small molecule oral TPH inhibitor Limits rate limiting enzyme tryptophan hydroxlyase, converts tryptophan to 5-hyroxytryptophan High molecular weight inhibits it from crossing blood-brain barrier Tryptophan 5-Hydroxytryptophan Serotonin Serotonin stored in secretory granules Serotonin in blood 5-Hydroxyindoleacetic acid (5HIAA) in urine

30 Telotristat Ethyl With 250 mg dose = 29% reduction in daily bowel movement

31 Reduction of u5hiaa

32 CARCINOID CRISIS Life threatening form of carcinoid syndrome that may be triggered by tumour manipulation: Biopsy, surgery Release of overwhelming amount of biologically active compounds Wide blood pressure fluctuations: mostly hypotension Flushing, Diarrhea, Tachycardia, Arrhythmias, Bronchospasms, Altered mental status Prevention Pre-op administration of octreotide (300mcg sc) Octreotide infusion protocol Treatment Support BP with octreotide 300 mcg iv + infusion of octreotide + plasma

33 Carcinoid heart disease: pathology Pathology: Thickening of right heart valves due to formation of fibrotic plaques: secondary to serotonin Affects valve function Leads to valve insufficiency, heart failure Involvement of left side of heart uncommon Commonly associated with chronic elevations of 5 HIAA

34 QUESTION In addition to symptom control what are the goals of starting a SSA? A. Tumour growth control B. Biochemical control C. Quality of Life D. All of the above

35 QUESTION In addition to symptom control what are the goals of starting a SSA? A. Tumour growth control B. Biochemical control C. Quality of Life D. All of the above

36 Tumour Control Somatostatin analogues SSAs Direct action via sstr 2 stimulation Indirect action Cell cycle arrest Apoptosis Inhibit IGF-1 (antiapoptotic hormone) Inhibit growth factors and trophic hormone secretion Inhibit angiogenesis Modulate the immune system IGF-1, insulin-like growth factor-1; SSAs, somatostatin analogues; sstr 2, somatostatin receptor subtype 2 Oberg. Clin Oncol. 2012;24:

37 SOMATOSTATIN ANALOGUES TWO PHASE III TRIALS

38 PROMID Study Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine MIDgut Tumors: A Report from the PROMID Study Group To evaluate the antiproliferative effect of octreotide LAR Phase III, randomized, double-blind, placebo-controlled Nonregistration trial 18 centres in Germany ( ) 39 Rinke A et al. J Clin Oncol 2009;27:

39 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 non- functioning RANDOMIZATION (1:1) Octreotide LAR 30 mg im every 28 days Placebo im every 28 days Treatment until CT/MRI documented tumour progression or death Primary endpoint: Time to tumour progression (blinded central review) Secondary endpoints: objective response rate, survival, quality of life, safety 40 Rinke A et al. J Clin Oncol 2009;27:

40 Octreotide LAR 30 mg Significantly Prolongs Time to Tumour Progression Compared with Placebo 66% reduction in the risk of tumour progression HR=0.34; 95% CI: ; P= Octreotide LAR 30 mg: 42 patients / 26 events Median TTP = 14.3 months [95% CI: ] Proportion without progression Placebo: 43 patients / 40 events Median TTP = 6.0 months [95% CI: ] 41 Rinke A et al. J Clin Oncol 2009;27: Time (months) Based on the conservative ITT analysis

41

42 PROMID Summary Lead to adoption of early SSA use in the clinical guidelines Octreotide LAR 30 mg significantly improves TTP in patients with metastatic well-differentiated midgut NETs 66% reduction of the risk of disease progression with octreotide LAR 30 mg vs placebo Improved TTP occurred regardless of functional status Later analyses, eg, survival, will be confounded by the subsequent crossover Accrual stopped after interim analysis with subsequent unblinding Octreotide LAR 30 mg was offered to patients in the placebo arm 43 Rinke A et al. J Clin Oncol 2009;27:

43

44 CLARINET: Study Design Study design: Phase 3, 96-week, randomized, double-blind, placebo-controlled, multicenter study (14 countries: the US, India, and 12 European countries) Population: Treatments: N=204 adults with well - or moderately differentiated, metastatic, and/or locally advanced un-resectable GEP-NETs, and Ki-67 <10% Lanreotide Autogel 120 mg (fixed dose) vs. placebo every 28 days Primary Endpoint = PFS weeks Scan 1 Scan 2 1:1 Lanreotide Autogel SC 120 mg q28 days Placebo SC q28 days GEP-NETs, gastroenteropancreatic neuroendocrine tumors; SC, subcutaneous (baseline) Study visits (weeks) Key Differences: Endpoint, Ki 67 < 10%, Positive octreotide scan, included GI and pnets, higher hepatic tumour load, known stable disease at the time of enrolment Caplin ME, et al. N Engl J Med. 2014;371(3):

45 CLARINET: Primary Efficacy Endpoint (PFS) Patients alive and with no progression (%) Progression-free survival (ITT population*) Lanreotide 32 events, 101 patients Median PFS not reached Placebo 60 events,103 patients Median PFS= 18.0 months [95% CI: 12.1, 24.0] Lanreotide 120 mg vs. PBO P <0.001 HR=0.47 [95% CI: 0.30, 0.73] 62% 22% Time (months) Numbers of patients at risk of death or PD Data are from the ITT population. P-value derived from stratified log-rank test; HR derived from Cox proportional hazards model. HR, hazard ratio; ITT, intention to treat; PBO, placebo; PD, progressive disease; PFS, progression-free survival. Caplin ME, et al. N Engl J Med. 2014;371(3): Key point : stable disease at the time of enrolment

46 CLARINET Summary CLARINET is the first Phase III, randomized, double-blind, placebo-controlled clinical trial using PFS as the primary endpoint in a combined PNET and GI-NET population 53% reduction in the risk of tumor progression or death Prolonged PFS in midgut and pancreatic NETs Effective in patients regardless of tumor grade (G1 or G2) or hepatic tumor volume G1, grade 1; G2, grade 2; GI-NETs, gastrointestinal neuroendocrine tumors; PNETs, pancreatic neuroendocrine tumors; PFS, progression-free survival; SSA, somatostatin analog. Caplin ME, et al. N Engl J Med. 2014;371(3):

47 Side effects of Somatostatin Analogs Mild fatigue GI disorders diarrhea, abdominal pain, nausea, constipation, flatulence Headaches Cholelithiasis Metabolism and nutrition (hyperglycemia) Somatostatin analogues can inhibit the secretion of insulin and glucagon Injection-site localized pain Test dose Octreotide 100 mcg SC Both companies have a home injection program Both companies have Health Canada indication for symptoms

48 Inclusion in SSA trials Octreotide Lanreotide Site Mid gut Mid gut, Hind Gut, PNETs Differentiation Well Well to Moderate Ki67 95% of patients had Ki67 <2% Ki67% <10%, or Mitotic index 2mitosis/10 HPF Progression Documented tumour progression 96% had NO tumour progression within 3-6 mns before starting trial SSR+ Octreotide scan Functioning 70% positive All positive Functioning and Nonfunctioning Non-functioning tumours (allowed gastrinomas on PPI) Prior treatment Treatment naïve patients IFN, chemo > 6 months pre study 84% had no prior treatment QOL Comparable both groups Quality of not affected

49 What about watchful waiting? Asymptomatic, advanced, unresectable GI NETs small volume disease Discuss watchful waiting PROMID Octreotide PLACEBO group: TTP 6 months CLARINET Lanreotide PLACEBO group: PFS 18 months

50 When you are cautious about Watch and Wait Progression means clinical deterioration Elderly with small bowel primary seen on imaging and non-operable due to co-morbidity NETs with G2 disease approaching Ki67= 20% Two scans in short interval showing progression Patient clearly not comfortable with approach

51 Case DG Went surgery unable to resect Bypass + More Omental disease than expected: Well differentiated NET; Ki67 2%; Mitosis 1/10HPF Cholecystectomy WHY DID THEY DO THIS? Symptoms improved initially on Octreotide LAR 30 mg q 4 weeks, Breakthrough symptoms for approximately 5-6 days prior to next injection WHAT DID WE DO?

52 Case DG Patient on Sandostatin LAR 30mg q 3 weeks better symptom control and growth is stable for 2 years. Imaging showed mild progression in liver and peritoneal mets. Also, new scattered bone lesions. Chromagranin 432-> 650; Urine 5HIAA -> 420 ->530 WHAT DID I DO NEXT? SYSTEMIC Treatment Continue to watch/monitor LIVER DIRECTED THERAPY

53 Options Systemic Increase dose of Octreotide LAR? Adding IFN or Bevacizumab to Octreotide? Start Cisplatin and Etoposide q 3 weeks? Send for PRRT (Peptide Receptor Radionucleotide therapy) treatment? Everolimus (as per RADIANT 4 trial)

54 Systemic Options Increase dose of Octreotide LAR? Small case series suggest some activity NETTER trial PFS in higher SSA group = 8 months, RR was 3% Adding IFN or Bevacizumab to Octreotide? Negative trials for improving PFS Start Cisplatin and Etoposide q 3 weeks? This was not behaving as poorly differentiated

55 What to use after progressing on SSA? Peptide Receptor Radionuclide Therapy (PRRT) vs Targeted Therapy

56 Slide 4 Presented By Jonathan Strosberg at 2016 ASCO Annual Meeting

57 Main Inclusion Criteria Patients 18 years of age Metastatic or locally advanced, inoperable, histologically proven, midgut NET Ki67 index 20% (Grade 1-2) Progressive disease (RECIST Criteria 1.1 centrally confirmed) on uninterrupted fixed dose of octreotide LAR (20-30 mg every 3-4 weeks) Somatostatin receptor positive disease Karnofsky Performance Score 60 Including functioning and non-functioning Presentation Presidential Session II of the 18th ECCO 40th ESMO European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna 61

58 Netter Trial Increased SSA vs PRRT Progression-Free Survival N = 229 (ITT) Number of events: Lu-Dotatate: 23 Oct 60 mg LAR: 68 Hazard ratio: 0.21 [ ] p < % reduction in the risk of disease progression/death Median PFS Sandostatin alone 8.4 months vs. Median PFS at 30 months not yet reached RESPONSE RATE 18% All progressions centrally confirmed and independently reviewed for eligibility (SAP) 62

59 PRRT in Ontario CCO Clinical Trial Progressive metastases in last 6 months Not suitable for curative therapy ECOG 2 Ki67 30% Serum Creatinine 150µmol/l GFR 30ml/min Hb 90g/l WBC 2x10 9 /l Platelet 100x10 9 /l Total bilirubin 5xULN ALT 5xULN AST 5xULN Alkphos 5xULN London Hamilton PMH Sunnybrook Ga68 PET part of trial If prior XRT, <25% of bone marrow irradiated Target lesion not radiated within past 12 weeks

60 Everolimus Targeted Therapy

61 What about systemic therapy for progressing well RADIANT 2 Pavel, Lancet 2011 differentiated NETs?

62 RADIANT-2 (Pavel, 2011) Previous treatment permitted, multiple disease sites, low or intermediate grade, history of secretory symptoms Everolimus 10mg/day + Octreotide LAR 30 mg i.m., q4w Placebo + Octreotide LAR 30 mg i.m., q4w Median PFS: 11.3 months (Placebo) 16.4 months (Everolimus) HR = % CI: p = (not significant) RADIANT-4 (Yao, 2016) Advanced (prior treatment & treatment naïve), lung or GI NETs, low or intermediate grade, non-secretory Everolimus: 10 mg.day p.o. Placebo Median PFS: 3.9 months (Placebo) 11.0 months (Everolimus) HR = % CI: p <

63 RADIANT-4: Study Design Target HR for PFS of 0.59; 91% power Patients with advanced, progressive, nonfunctional NET of lung or GI origin (N = 302) Absence of active symptoms or any history of CS Pathologically confirmed advanced disease Radiologic disease progression in 6 months R A N D O M I Z E D 2:1 Everolimus 10 mg/day n = 205 Treated until centrally confirmed PD or intolerable toxicity Placebo n = 97 Stratified by: Prior SSA treatment (yes vs. no) Tumor origin (stratum A vs. B) a WHO PS (0 vs. 1) Endpoints Primary: PFS (central) Key Secondary: OS a Two strata: Stratum A appendix, cecum, 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: For distribution in response to an unsolicited request for medical information subject to local NP4 approval. 67

64 RADIANT-4 Primary Endpoint: PFS by Central Review PFS probability (%) Everolimus Placebo % reduction in the relative risk of progression or death with everolimus vs. placebo HR = 0.48 (95% CI: 0.35, 0.67); P < Kaplan-Meier medians Everolimus: 11.0 months (95% CI: 9.2, 13.3) Placebo: 3.9 months (95% CI: 3.6, 7.4) 30 Censoring times 20 Everolimus (n/n = 113/205) 10 Placebo (n/n = 65/97) No. of patients still at risk Time (months) Reproduced with permission from Yao JC et al. Lancet. 2016;387: P-value obtained from the stratified one-sided log-rank test; HR obtained from stratified Cox model. For distribution in response to an unsolicited request for medical information subject to local NP4 approval. 68

65 RADIANT-4: PFS HR by Primary Tumor Origin: Retrospective Analysis, Central Review Subgroups a No. HR (95% CI) Lung ( ) GI b ( ) NET of unknown primary ( ) Everolimus Better Placebo Better Reproduced with permission from Yao JC et al. Lancet. 2016;387: HR obtained from unstratified Cox model. a One patient with thymus as primary tumor origin was not included. b Stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum are grouped under GI. For distribution in response to an unsolicited request for medical information subject to local NP4 approval. 69

66 Travel PRRT (NETTER trial) Travel to expert site Hospitalized for 1-3 days Everolimus (Radiant 4 trial) No travel Primary tumour Site Mid Gut GI tract/ Lung Both subgroups benefit Ki67% NETTER trial allowed <20% Some PRRT programs <30% Grade 1 or 2 Functioning Tumour Prior Treatment Kidney Function Both functioning and NON-fnx (MUST be Somatatostatin receptor positive) 41% (PRRT) and 45% (control) had other systemic treatment Cr < 150 or GFR needs to be >50 ml/min ONLY NON-functioning About 20% had prior PRRT treatment Data on Everolimus in borderline kidney fnxpatients? Myelosuppression Grade 3/4 = 9% May have long term outcomes in 1-3% patients Do you need tumour shrinkage Reversible Grade 3/4 = 13% RR = 18% PR = 2% Disease Control = 81%

67 Canadian Consensus Recommendation Systemic Therapy for Metastatic or Unresectable Disease Disease Type Non-progressive disease Progressive disease treatment naïve Progressive disease on SSA Therapy SSR Positive disease via In-111 Octreotide or Ga-68 DOTA-TATE imaging (for PRRT) Treatment Plan For GI NETs without evidence of carcinoid syndrome, initiation of SSA treatment or expectant management are both appropriate therapeutic options Single agent SSAs (Octreotide LAR 30 mg, i.m. q4w or lanreotide autogel 120 mg, s.c., q4w: C1) Single agent use of everolimus (10 mg/day: C1) Everolimus in combination with SSAs is an additional option Peptide receptor radionuclide therapy (PRRT) 177 Lu DOTA-TATE should be considered for mid-gut NETs (C1) 177 Lu DOTA-TATE is an option for GI NETs If 177 Lu DOTA-TATE is unavailable, 90Y-DOTA- Octreotide is an option Patients receiving PRRT, particularly 90Y-DOTA- Octreotide are at risk of kidney toxicity and aminoacid protection to reduce toxicity is required Singh et al, Cancer Treatment Reviews 2016

68 Summary Therapeutic options for Mid-gut NETs are increasing Sequencing of therapy is becoming better delineated 1 st line treatment with SSA (lanreotide or sandostatin) should be considered for both functional and nonfunctional disease Further therapy can be targeted to disease distribution Resection of primary Targeted liver therapy only disease where possible: surgery, RFA, TACE Systemic therapies include PRRT vs Everolimus Key is individualize right treatment at the right time National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors. 2015:1-108.

69 Case Study Pancreatic Neuroendocrine Tumours (NETs) What is the team thinking?

70 Case RV 52 year old male previously well Present with 2-3 month history abdominal pain, cramps CT scan in emergency: 4cm mass pancreas +? liver lesions MRI: 4.2 cm mass pancreas + at least liver lesions (5-7 mm); enlarged peri-portal LNs No functional symptoms Urine 5HIAA normal, Chromagranin high 215 PATH: well differentiated neuroendocrine tumour: FNA can not comment on mitosis or Ki67 WHAT DO I DO NOW?

71 Case RV Repeat biopsy: 2 Mitosis/10 HPF with Ki67 10% Octreotide scan: negative Presented at tumour board: not candidate for liver directed therapies or surgery Liver tests: AST, ALT, Bilirubin normal

72 CASE RV What systemic treatment have RCT evidence? Somatostatin analogue Sunitinib 37.5 mg po daily Strepto based chemotherapy Everolimus 10 mg po daily Temozolamide + Capecitabine PRRT treatment Cisplatin + Etoposide

73 CASE RV What systemic treatment have RCT evidence? Somatostatin analogue Sunitinib 37.5 mg po daily Strepto based chemotherapy Everolimus 10 mg po daily Temozolamide + Capecitabine PRRT treatment Cisplatin + Etoposide

74 Is there Progression-free a role for Survival, Somatostatin According Subgroups (Intention-to-Treat analogues Population). in PNETs tumour control Caplin ME et al. N Engl J Med 2014;371:

75 Is there a role for targeted therapy in progressive PNETs?

76 Indolent to Moderately Progressive Disease PRIMARY GOAL RECOMMENDED TREATMENT OPTION Stabilization Targeted Therapy Both everolimus and sunitinib are considered effective and acceptable therapies o Everolimus o RADIANT 3 trial patients with advanced-, low-, or intermediategrade pnets. o Median PFS: 11 months (everolimus) vs 4.6 months (placebo) (HR, 0.35; 95 % CI ; P<0.001) Yao, NEJM, 2011

77 Indolent to Moderately Progressive Disease PRIMARY GOAL RECOMMENDED TREATMENT OPTION Stabilization Targeted Therapy Both everolimus and sunitinib are considered effective and acceptable therapies osunitinib o171 patients with advanced well-differentiated pnets omedian PFS: 11.4 months (sunitinib) vs 5.5 months (placebo) (HR, 0.42; 95 % CI ; P<0.001) Raymond NEJM 2011

78 Similarities in PNET Targeted Trials Advanced, or metastatic Disease progression in last 12 months Placebo trials, allowed cross-over Well, differentiated (low-intermediate grade) Allowed prior therapy: including Somatostatin Analogue Both controlled for cross-over and showed a likely survival benefit Quality of life Sunitinib data: Prospective: No difference compared to Placebo except diarrhea Everolimus: (Pavel Targ Oncol May 2016) N=126 PNET patients on Expanded Access: no change compared to baseline

79 Everolimus PNET: Survival Rank-Preserving Structural Failure Time 85% of patients on Placebo arm cross over 12 months 24 months Everolimus 82.6% 67.7% HR = 0.60 RPSF Placebo arm 74.9% 55.6% Yao JCO 2016

80 OS at 5 Years After Study Closure With and Without Adjustment for Crossover Overall Survival Probability (%) n mos, mo (95% CI) ITT Analysis Sunitinib ( ) Placebo ( ) RPSFT Model Placebo ( ) Time (months) CI=confidence interval; ITT=intent-to-treat; mos=median overall survival; RPSFT=rank-preserving structural failure time E Raymond, ENETS

81 Indolent to Moderately Progressive Disease Canadian Consensus Recommendation, 2014 The choice of agent should be based on: Patient preference Comorbidities Toxicity profiles Tolerance Availability Sequential therapy should be considered

82 How to choose? Side effect profile Everolimus GRADE 3/4 toxicity Stomatitis 7% Anemia 6% Hyperglycemia 5% Thrombocytopenia 4% Diarrhea 3% Fatigue 2% Pneumonitis 2% Think twice - Uncontrolled Diabetic - Lung disease worried about pneumonitis Use it in Insulinoma Sunitinib GRADE 3/4 Toxicity Neutropenia 12% Hypertension 10% Palmer-planter erythrodyesthesia 6% Diarrhea 5% Think twice - Uncontrolled HTN - Hand/foot going to affect mobility

83 A randomized phase II study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN Cancer Research Group (E2211) Presented By Pamela Kunz at 2018 ASCO Annual Meeting

84 E2211 Study Design Presented By Pamela Kunz at 2018 ASCO Annual Meeting

85 Progression Free Survival Presented By Pamela Kunz at 2018 ASCO Annual Meeting

86 Overall Survival Presented By Pamela Kunz at 2018 ASCO Annual Meeting

87 E2211 Conclusions Presented By Pamela Kunz at 2018 ASCO Annual Meeting

88 Take home points Pancreatic NETs can behave more aggressively than mid gut NETs Agents of choice based on clinical trial data: SSA, Everolimus, Sunitinib, now Cape/Tem No consensus on when to give chemotherapy, but should be considered for rapidly progressive, Ki67 >55%