Teresa Alonso Gordoa Servicio Oncología Médica Hospital Universitario Ramón y Cajal

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1 Teresa Alonso Gordoa Servicio Oncología Médica Hospital Universitario Ramón y Cajal

2 Incidence per 100,000 EPIDEMIOLOGY Incidence rates of neuroendocrine tumors by primary tumor site NET Site Lung Apendice Gastric Colon Small intestine Rectum Cecum Pancreas Year

3 EPIDEMIOLOGY Grade I Grade II Grade III Sackstein P, et al. Seminars Oncology 2018, In press

4 EPIDEMIOLOGY Halperin D, et al. Lancet oncol 2017

5 EPIDEMIOLOGY Incidence of total NETs and carcinoid syndrome, Percentage of patients with incident NETs diagnosed with carcinoid syndrome. Halperin D, et al. Lancet oncol 2017; 18:

6 EPIDEMIOLOGY Overall survival of patients diagnosed with NET, Entire NET cohort Metastatic grade 1 2 small bowel NETs Halperin D, et al. Lancet oncol 2017; 18:

7 SYMPTOMS AT DISEASE PRESENTATION 23/11/ Halperin DM, Kulke MH & Yao JC. Ann Rev Med 2015

8 CARCINOID SYNDROME Serotonin and other hormones play a central role. Incidence 8-35% of patients with NETs mainly with liver metastasis, but not only. Symptoms are different among patients Yao JC, Hassan M, Phan A et al. J Clin Oncol 2008;26: Oberg K, Akerström G, Rindi G et al. Ann Oncol 2010;21(suppl 5): v223 v227 Kulke, MH, Mayer RJ. Carcinoid tumors. NEJM 1999;340(11):

9 THERAPEUTIC AGENTS THAT HAVE BEEN EVALUATED IN PATIENTS WITH FUNCTIONING NET

10 ENDPOINTS SYMPTOMS CONTROL TUMOR GROWTH CONTROL AVOID COMPLICATIONS QUALITY OF LIFE WINDOW OF THERAPEUTIC OPPORTUNITY SOCIAL/FAMILY/LAB OR ENVIRONMENT HORMONE SECRETION CONTROL SURVIVAL IMPROVEMENT

11 TREATMENT FOR NETs SURGERY LIVER DIRECTED THERAPIES SOMATOSTATIN ANALOGUES RADIONUCLIDES INTERFERON EVEROLIMUS/SUNITI NIB CHEMOTHERAPY TELOTRISTAT

12 Toumpanakis C, Caplin ME. Update on the Role of Somatostatin Analogs for the Treatment of Patients With GEP NET. Semin Oncol 2013 SOMATOSTATIN ANALOGES IGF-1 K + SRIF Voltage SSTR1-5 IGF-1R Ca 2+ channel K + channel Ca 2+ channel Signaling Ca 2+ Gβ Gα Gγ PLCβ IP3 Hormona Secretion camp AC PTPase SHP-1 SHP-2 PTP-γ Caspase 8 Wild type p53 Bax phi Endonuclease Apoptosis ERK 1/2 ERK 1/2 P27 kip1 Cell Growth Ca 2+ Secretion

13 SOMATOSTATIN ANALOGES Rindi G & Wiedenmann B. Nature Reviews Endocrinology, 2012 Modlin IM, Latich I, Kidd M et al. Clin Gastroenterol Hepatol 2006;4:

14 SOMATOSTATIN ANALOGES Rubin J, Ajani J, Schirmer W et al. J Clin Oncol.1999;17:

15 SOMATOSTATIN ANALOGES -Phase III -Well-differentiated metastatic midgut NETs (Ki67 1-2%) -Functioning and non functioning mttp= 14.3 (O) vs 6.0m (P) (HR0,34; p<0.001 Caplin ME, et al. N Engl J Med 2014;371:224-33

16 SOMATOSTATIN ANALOGES -Phase III -Well-differentiated metastatic midgut NETs (Ki67 1-2%) -Functioning and non functioning Caplin ME, et al. N Engl J Med 2014;371:224-33

17 SOMATOSTATIN ANALOGES -Phase III -Well-differentiated metastatic NETs (Ki67 <10%) -Non functioning Rinke A et al. J Clin Oncol 2009;27: mpfs= NR(L) vs 18.0m (P) (HR0.47, p<0.001)

18 SOMATOSTATIN ANALOGES -Phase III -Well-differentiated metastatic NETs (Ki67 <10%) -Stable Carcinoid Syndrome OPEN LABEL (IOB) PHASE (32 weeks) Fisher GA, et al. Endocr Practice 2018 LONG TERM OPEN LABEL EXTENSION ( 2 years)

19 SOMATOSTATIN ANALOGES -Phase III -Well-differentiated metastatic NETs (Ki67 <10%) -Stable Carcinoid Syndrome Fisher GA, et al. Endocr Practice 2018

20 Courtesy of Dr E. Grande. Presented at ESMO Beaumont JL, et al. Pancreas 2012 Kvols L, et al. Endocr Relat Cancer 2012 RESISTANCE TO SSA Octreotide fails in carcinoid syndrome control in approx 71% of patients after 36 moths of treatment. 100% 80% 60% 40% 20% 0% 86% 74% 50% 29% % of patients still responding over time (months)

21 RESISTANCE TO SSA Mechanisms of resistance Different phosphorylation patterns Type of β-arrestins Homo/Heterodimers Antibody formation Observations In SSTR2 different phosphorylation patterns have been described over 4 threonine residues (Thr353, Thr354, Thr356, and Thr359) with octreotide and only 2 threonine residues (Thr356 and Thr359) with pasireotide. This phosphorylation is mediated by G protein-coupled receptor kinases (GRK) 2 and 3, whose intracellular levels are variable. The inhibition of these enzymes results in a reduction of approximately 40% of SSTR2 phosphorylation. There are two major subtypes of β-arrestins, A and B. Replacement of SSTR2 on the cell surface depends on β-arrestin (Type B) internalization, once bound to the phosphorylated endosomal vesicle, produces rapid receptor internalization. SSTR3 and SSTR5 are also β- arrestin (Type A) dependent receptors, but their junction is less stable so the internalization is less efficient. On the contrary, SSTR1 and SSTR4 are not depending on this molecule for internalization. Different types of receptors co-exist in the same cell surface, enabling the formation of homo- and heterodimers between them, such as the heterodimerization between SSTR5 and SSTR1 Creation of antibodies against somatostatin analogs, decreasing their effectiveness. Molina-Cerrillo J, Alonso-Gordoa T, Saez O & Grande E. The Oncologist. 2016

22 ENETS GUIDELINES Pavel M, et al. Neuroendocrinology, 2016

23 LOCAL TREATMENTS: SURGERY AND LOCOREGIONAL TREATMENT Surgery can be curative if it reaches R0. Arterial hepatic embolization/radioembolization can be usefull in selected patients Use of those techniques depends on tumoral size, number of metastases, anatomic viability and surgeon/radiologist experience. May help in symptoms relief. Toumpanakis C, et al. Brest Pract Res Clin Endocrinol Metab. 2007

24 INCREASE SSA DOSE Strosberg J. Gastrointest Cancer Res 6:81 85

25 INTERFERON Symtomatic hormone response: 40-70%. Disease control rate: 50-60%, OR= 10-15%. Alonso-Gordoa T, et al E. Eur J Endocrinol 2015

26 EVEROLIMUS RADIANT-2 Patients with advanced NET and history of carcinoid syndrome (N=429) - G1 or G2 histology - rdp within 12 months - Prior therapy allowed - WHO PS 2 RANDOMIZED 1:1 Everolimus 10 mg/day + Octreotide LAR 30 mg q28d (N=216) Placebo + Octreotide LAR 30 mg q28d (N=213) Everolimus 10 mg/day + Octreotide LAR 30 mg q28d (N=143) Double-blind phase Primary analysis PD Open-label everolimus at progresssion and unblinding Pavel ME, Lancet 2011 Yao JC, J Clin Oncol 2012 (Abstr 157)

27 EVEROLIMUS RADIANT-2 Changes in biomarker concentrations over time by treatment group Cromogranin A 24 hour urine 5HIAA Pavel ME, Lancet 2011 Yao JC, J Clin Oncol 2012 (Abstr 157)

28 RADIONUCLIDES

29 RADIONUCLIDES NETTER-1 Aim Design Evaluate the efficacy and safety of 177 Lu-Dotatate (Lutathera ) plus Octreotide30 mg compared to Novartis Octreotide LAR 60mg (off-label use) 1 in patients with inoperable, somatostatin receptor positive, midgut NET, progressive under Octreotide LAR 30mg (label use) International, multicenter, randomized, comparator-controlled, parallel-group Treatment and Assessments Progression free survival (Recist criteria) every 12 weeks Dose 1 Dose 2 Dose 3 Dose 4 Baseline and Randomization n = 115 n = administrations of 7.4 GBq of 177 Lu-Dotatate every 8 weeks + Octreotide30 mg Octreotide LAR 60mg every 4 weeks 5 Years follow up 1. FDA and EMA recommendation Presentation Presidential Session II of the 18th ECCO 40th ESMO European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna

30 Strosberg J, et al. JCO 2018 RADIONUCLIDES

31 RADIONUCLIDES TTD was significantly longer in the 177Lu-Dotatate arm compared with the octreotide arm in diarrhea Strosberg J, et al. JCO 2018

32 TELOTRISTAT Molina-Cerrillo J, Alonso-Gordoa T, Saez O & Grande E. The Oncologist. 2016

33 TELOTRISTAT Kulke M. ESMO Kulke M. et al. J Clin Oncol 2016

34 TELOTRISTAT Kulke M. et al. J Clin Oncol 2016

35 TELOTRISTAT Similar design that TELESTAR, but including patients with lesssevere gastrointestinal symptoms. Endpoints: Efficacy an safety. Pavel et al. Presented NANETS 2016

36 CONCLUSIONS: BUILDING ON SUCCESS Carcinoid syndrome is lead by serotonin activity and can significantly deteriorate the quality of life of patients. Treatment with SSA is effective but the symptomatology of patients resist along the treatment. There are some drugs potentially effective in carcinoid syndrome, but further research is required: involvement in antitumor effect. Telotristat is a drug which inhibits peripherally secretion of serotonin, effective in refractory carcinoid syndrome. Pending questions: Adequate dose, antitumor effect, long term efficacy and safety (TELEPATH), durability of responses, prevention of fibrosis...

37 MUCHAS GRACIAS POR VUESTRA ATENCIÓN