NET MASTERCLASS 2016 An interactive workshop

NET MASTERCLASS 2016 An interactive workshop Νέες Θεραπευτικές Επιλογές ΝΕΤ εντέρου Πώς ξεκινάμε, πώς συνεχίζουμε Αυγερινός Αντώνης PhD FEBG Επιμελητής Α Γαστρεντερολογίας ENETS-ESDO ESMO Full Member Γαστρεντερολογικό Τμήμα ΓΝΘ Γ.Παπανικολάου

Incidence per 100,000 for neuroendocrine tumors Επιδημιολογικά δεδομένα-ηπα In the United States, the incidence of NETs is rising Increased incidence between 1973 and 2004 from 1.09 to 5.25 cases per 100,000 persons Incidence of all malignant neoplasms Incidence of all neuroendocrine tumors Incidence per 100,000 for all malignant neoplasms Year Yao, JC, Hassan M, Phan A, et al. J Clin Oncol. 2008:26(18):3063-3072

Incidence per 100,000 Επιδημιολογικά δεδομένα-ηπα 5-fold increase in occurrence of NETS over past 30 years United States SEER data Lung Rectum Small Bowel Stomach Pancreas Cecum Colon Appendix Year Yao, JC, Hassan M, Phan A, et al. J Clin Oncol. 2008:26(18):3063-3072

Η τοπικά προχωρημένη-μεταστατική νόσος είναι συχνή στην πρωτοεμφανιζόμενη νόσο. Distant metastases Regional spread * This data is of the cases in which stage was reported. 20% of cases did not provide disease stage information. Data from an analysis of 28,515 cases of NET identified in the SEER registries Yao JC, et al. J Clin Oncol. 2008;26:3063 3072.

Νευροενδοκρινείς όγκοι. 1.Ορισμοί 2.Ταξινόμηση Διαφοροποίηση(Grading) Σταδιοποίηση (Staging) 3.Διαφοροποίηση ανάλογα με την εντόπιση.

Chance of survival Συσχέτιση επιβίωσης και διαφοροποίησης του όγκου 1.0 0.8 0.6 G1 G2 Grade Mitotic count (10 HPF) Grading NET* Ki67 index (%) 0.4 0.2 G1 vs G2 G1 vs G3 G2 vs G3 P = 0.040 P < 0.001 P < 0.001 G1 2 2 G2 3 20 3 20 G3 > 20 > 20 0.0 G3 0 50 100 150 200 250 Time (months) * ENET and AJCC grading system Rindi G, et al. Virchows Arch. 2006;449:395-401. Rindi G, et al. Virchows Arch. 2007;451:757-762. Pape UF, et al. Cancer. 2008;113:256-265.

TNM ταξινόμηση των GEP-NETs Stage 0* Τis N0 M0 Stage I T1 N0 M0 Stage IIa T2 N0 M0 IIb T3 N0 M0 Stage IIIa T4 N0 M0 IIIb Any Τ Ν1 Μ0 Stage IV Any Τ Any Ν Μ1 Classification according to the anatomic origin ENETS 2009

Probability of survival Συσχέτιση επιβίωσης και TNM σταδιοποίησης. 1.0 0.8 Stage I Stage II 0.6 0.4 0.2 Stage III Stage IV I vs II P = 0.227 I vs III P = 0.048 I vs IV P < 0.001 II vs III P = 0.171 II vs IV P < 0.001 III vs IV P = 0.004 ENET TNM Staging 0.0 Pape UF, et al. Cancer. 2008;113:256-265. 0 50 100 150 200 250 Months N = 202 cases: gastric (48), duodenum (23), pancreatic (131); n = 193.

Γενετική διαφοροποίηση. Pancreas NET 1.Germiline mutations (MEN1,VHL,NF1,TSC1) 2.Somatic mutations (MEN1,DAXX/ATRX VHL TSC1) 3.Chromosomal alterations Chromosomal instability Ileal NET FIEC?Ch 18 CDKN1B, APC No ΔΙΑΦΟΡΟΠΟΙΗΣΗ ΘΕΡΑΠΕΙΑΣ

Biology of tumor (WHO classification, grading) Extent of disease (TNM, stage)

Η χρωμογρανίνη(cga) ως προγνωστικός δείκτης επιβίωσης. Percent Concentrations are indicative of tumour burden 1 5-year survival based on CgA concentration at diagnosis 80 An independent predictor of survival outcome 2,3 60 40 20 1. Eriksson B, et al. Digestion. 2000;62(suppl 1):33-38. 2. Ardill JES, Erikkson B. Endocr Rel Cancer. 2003;10(4):459-462. 3. Janson EMT, Öberg KE. Baillieres Clin Gastroenterol. 1996;10(4):589-601. 0 Low CgA 5000 μg/l High CgA > 5000 μg/l

Disease burden Current Management of Grade 1&2 P-NETs Bulky slowgrowing Low volume slow Medium Bulky aggressive Low volume aggressive Available options: Observation. Somatostatin analogs. Everolimus. Sunitinib. Streptozocin-based chemotherapy. Temozolomide-based chemotherapy. PRRT with 177 Lu-SSA. Liver directed therapy. Aggressiveness Courtesy J. Yao

Κλινική σταδιοποίηση της νόσου. Θεραπείες 1 ης κ 2 ης γραμμής. Ασθενής με σταθεροποιημένη νόσο. Ασθενής με πρόοδο νόσου. Πρωτοθεραπευόμενος ασθενής Προόδος νόσου η συνδρόμου υπό θεραπεία

Θεραπευτικός στόχος. Ελεγχος συμπτωμάτων σε λειτουργικούς όγκους. Αντινεοπλασματική θεραπεία ελέγχου της αύξησης του όγκου.

ΘΕΡΑΠΕΥΤΙΚΕΣ ΜΕΘΟΔΟΙ NETs somatostatin analogues, a-interferon, m-tor, VEGFR inhibitors) Χημειοθεραπεία Ενδοσκοπική και Χειρουργική θεραπεία. PRRT Τοπικοπεριοχικές θεραπείες: RFA, embolization, SIRT

Carcinoid syndrome: response to somatostatin analogues Clinical response 70-90% Biological response 35-75% Objective response 0-5%

Kulke MH,Hotsh D 18 th ECCO-40 Th ESMO European cancer congress Sept 2015 Abstract 37LBA

Αντινεοπλασματική δράση αναλόγων Σωματοστατίνης. Somatostatin DIRECT EFFECT INDIRECT EFFECT Octreotide sst 2 Arrest of cell cycle Cell death by apoptosis Inhibition of secretion of trophic factors Modulation of immune system (Natural killers) Inhibition of growth factors Inhibition of angiogenesis (VEGF) Buscail et al 1994, Sharma et al. 1998, Danesi et al. 1997, Albini et al. 1998, Pages et al. 1999, Florio et al 2003

Μελέτη PROMID Phase III Study G1,2 (WHO) only Gastrointestinal tumors

Proportion without progression Octreotide LAR significantly prolongs PFS Octreotide LAR vs placebo P=0.000072 HR= 0.34 [95% CI: 0.20 0.59] 1 0.75 Octreotide LAR: 42 patients / 26 events Median 14.3 months [95% CI: 11.0 28.8] 0.5 Placebo: 43 patients / 40 events Median 6.0 months [95% CI: 3.7 9.4] 0.25 0 0 6 12 18 30 36 42 48 54 60 66 72 78 Time (months) Based on the conservative ITT analysis

The PROMID Study: Octreotide LAR in Midgut NETs Tί μάθαμε; Lessons Octreotide LAR shows antitumor effect in : midgut tumors Low hepatic tumor burden (<10%) Grade 1 tumors Limitations The efficacy of SSAs is uncertain in : Non Midgut tumors Higher liver tumor burden Grade 2 tumors Progressive disease

CLARINET Aim Design Study aim and design CLARINET (Controlled study of Lanreotide Antiproliferative Response In NET)* To compare effect of lanreotide Autogel 120 mg vs. placebo on PFS in non-functioning enteropancreatic NETs International randomized double-blind placebo-controlled phase 3 study Screening 12 24 weeks Lanreotide Autogel 120 mg every 28 days (s.c.) CT/MRI scan 1 CT/MRI scan 2 1:1 randomization Placebo every 28 days (s.c.) 1 (Baseline) 12 24 36 48 72 96 Study visits (weeks) *ClinicalTrials.gov NCT00353496; EudraCT 2005-004904-35. PFS, progression-free survival; s.c., subcutaneous. Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33

CLARINET Study endpoints Primary endpoint PFS (time to death or PD) within 96 weeks of first injection PD assessed centrally with RECIST 1.0 PFS was also examined in pre-defined subgroups (e.g. tumour origin, tumour grade, and hepatic tumour volume) Key secondary endpoints Overall survival % patients alive and without PD at weeks 48 and 96 Time to tumour progression Quality of life % patients with 50% reduction in CgA* PK Safety *For subgroup of patients with baseline levels >ULN. CgA, chromogranin A; PD, progressive disease; ULN, upper limit of normal. Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33

CLARINET Patient population Adults with sporadic non-functioning* enteropancreatic NETs Well-/moderately differentiated tumours with Ki-67 <10% Tumours measurable according to RECIST 1.0 (centrally assessed) Unresectable locally advanced tumours or metastatic disease (or patients declined surgery) Target lesion(s) classified as grade 2 on somatostatin receptor scintigraphy No use of interferon, chemoembolization, or chemotherapy in previous 6 months, and SSA naïve (unless >6 months previously and <15 days in duration) *Including gastrinomas adequately controlled by proton pump inhibitors and NETs of unknown primary origin Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33

Patients alive and with no progression (%) CLARINET PFS (primary endpoint): significantly prolonged with lanreotide Autogel 120 mg vs. placebo with 53% risk reduction of disease progression or death with Somatuline 120mg versus placebo 100 90 Lanreotide Autogel 120 mg vs. placebo p<0.001 HR=0.47 [95% CI: 0.30, 0.73] 80 70 65% at 24 months 60 50 40 30 20 10 Lanreotide Autogel 120 mg 32 events/101 patients median, not reached during the 24 months Placebo 60 events/103 patients median, 18.0 months [95% CI: 12.1, 24.0] 33% at 24 months 0 0 3 6 9 12 18 24 27 Time (months) Numbers of patients at risk of death or PD 101 94 84 78 71 61 103 101 87 76 59 43 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. Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33 40 0 26 0

CLARINET PFS: therapeutic effect in pre-defined subgroups generally consistent with overall population Subgroup No. Hazard Ratio (95% Confidence Interval) All patients Tumour origin Midgut Pancreas Hindgut Other/unknown Tumour grade G1 tumour G2 tumour Hepatic tumour volume <25% >25% 204 73 91 14 26 141 61 137 67 0.47 (0.30 0.73) 0.35 (0.16 0.80) 0.58 (0.32 1.04) 1.47 (0.16 13.24) 0.21 (0.04 1.03) 0.43 (0.25 0.74) 0.45 (0.22 0.91) 0.34 (0.18 0.62) 0.45 (0.23 0.88) 0.0625 0.125 0.25 0.5 1 2 4 8 16 Lanreotide better Placebo better Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33

Patients alive and with no progression (%) CLARINET PFS (subgroups) effect in midgut tumors consistent with overall population 100 Midgut NETs (n=73) Lanreotide Autogel vs. placebo HR=0.35 [95% CI: 0.16, 0.80] Data from NEJM online appendix 90 80 70 60 50 40 30 Lanreotide Autogel 120 mg 8 events/33 patients median, not reached during the 24 months 20 Placebo 10 21 events/40 patients median, 21.1 months [95% CI: 17.0, NC] 0 0 3 6 9 12 18 24 27 Time (months) Numbers of patients at risk of death or PD 33 33 32 30 28 24 16 0 40 39 36 32 28 20 13 0 Time (months) Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33

Patients alive and with no progression (%) CLARINET Data from NEJM online appendix PFS (subgroups) effect in low and high hepatic tumour volume consistent with overall population 100 90 80 70 60 Hepatic tumour volume 25% (n=137) Lanreotide Autogel vs. placebo HR=0.34 [95% CI: 0.18, 0.62] 100 90 80 70 60 Hepatic tumour volume >25% (n=67) Lanreotide Autogel vs. placebo HR=0.45 [95% CI: 0.23, 0.88] Lanreotide Autogel 120 mg 18 events/39 patients median, 24.1 months [95% CI: 9.3, NC] 50 40 30 Lanreotide Autogel 120 mg 14 events/62 patients median, not reached during the 24 months 50 40 30 20 10 0 Placebo 41 events/75 patients median, 21.1 months [95% CI: 17.6, 24.4] 0 3 6 9 12 18 24 27 Time (months) Numbers of patients at risk of death or PD 62 58 56 52 50 43 75 73 69 63 52 38 HR derived from Cox proportional hazards model. 20 10 0 Placebo 19 events/28 patients median, 9.4 months [95% CI: 6.3, 12.0] 0 3 6 9 12 18 24 27 Time (months) 28 0 39 36 28 26 21 18 25 0 28 28 18 13 7 5 Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33 12 0 1 0

Patients alive (%) CLARINET Overall survival (secondary endpoint): no significant difference 100 90 80 CLARINET study (n=204) lanreotide Autogel or placebo (double-blind) Post-study survival phase: lanreotide Autogel (open-label extension study; n=88) or treatment not specified (local care) Data from NEJM online appendix 70 60 50 40 30 20 10 Patients originally randomized to: lanreotide Autogel 120 mg placebo Lanreotide Autogel 120 mg vs. placebo P=0.88 Patients originally randomized to lanreotide 19 deaths/101 patients Patients originally randomized to placebo 17 deaths/103 patients 0 0 12 24 36 48 60 72 84 Time (months) Numbers of patients at risk of death or disease progression 101 89 78 59 37 14 5 0 103 88 73 51 35 16 6 0 Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33

CLARINET Implications for clinical practice Lanreotide ATG 120mg/4W is associated with prolonged progressionfree survival among patients with advanced, grade 1 or 2 (Ki-67 <10%) enteropancreatic, somatostatin receptor positive neuroendocrine tumors with prior stable disease, irrespective of the hepatic tumor volume. CLARINET study represents the highest level of evidence demonstrating antiproliferative effects of Lanreotide Autogel 120 mg in patients with GEP NETs. CLARINET demonstrates a clear benefit of lanreotide Autogel 120 mg in the prevention of disease progression in the treated patients, i.e antiproliferative effect versus WW, the placebo arm being a surrogate of the WW strategy These efficacy data and its favorable safety profile support the place of lanreotide Autogel 120 mg early in the treatment algorithm of patients with GEP-NET Caplin M., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New Engl J Med 2014;371(3):224 33

Caplin M et al., Endocr Relat Cancer 2016, 23(3): 191-199.

Caplin M et al., Endocr Relat Cancer 2016, 23(3): 191-199.

Caplin M et al., Endocr Relat Cancer 2016, 23(3): 191-199.

Caplin M et al., Endocr Relat Cancer 2016, 23(3): 191-199.

Everolimus Εκλεκτικός αναστολέας mtor. Kινάση σερίνης-θρεονίνης, που επάγει το ενδοκυττάριο σήμα της διέγερσης μεμβρανικών υποδοχέων από αυξητικούς παράγοντες επιδρώντας: κυτταρικό πολλαπλασιασμό&ανάπτυξη μεταβολισμό αγγειογένεση

RADIANT-4 study design G1/G2 tumors Advanced, NF, NET of gastro-intestinal or lung origin N = 272 R A N D O M I ZE 1:1 Everolimus 10 mg/day + best supportive care n = 136 Placebo + best supportive care n = 136 PFS assessment until PD as determined by local radiology review Primary Endpoint: PFS by local radiological assessment (RA), (real time central RA secondary EP) HR target value/ PFS median: 0.59/ 5 to 8.5 months Interim analysis at 60% of PFS events Stratification by tumor site, WHO and prior SSA

Probability of Progression-free Survival (%) Primary Endpoint: PFS by Central Review 52% reduction in the relative risk of progression or death with everolimus vs placebo HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001 100 90 80 70 60 50 40 Kaplan-Meier medians Everolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43) 30 20 10 0 0 2 4 6 8 10 12 15 18 21 24 27 30 No.of patients still at risk Censoring Times Everolimus (n/n = 113/205) Placebo (n/n = 65/97) Months Everolimus Placebo 205 168 145 124 101 81 65 52 26 10 3 0 0 97 65 39 30 24 21 17 15 11 6 5 1 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;387:968-977.

PFS HR by Primary Liver Tumor Burden Per Central Review Liver Tumor Burden None No. 48 Hazard Ratio (95% CI) 0.49 (0.20-1.20) 10% 180 0.67 (0.45-1.00) >10%-25% 37 0.62 (0.20-1.93) >25% 35 0.18 (0.06-0.50) 0.1 0.4 1 10 Everolimus Better Placebo Better Hazard ratio obtained from unstratified Cox model Yao JC et al. Lancet 2016;387:968-977.

Probability of Overall Survival (%) Interim Overall Survival Analysis First interim OS analysis performed with 37% of information fraction favored the everolimus arm 100 90 Everolimus vs Placebo HR = 0.64 (95% CI, 0.40-1.05); P = 0.037 (NS)* Everolimus Placebo 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 15 18 21 24 27 30 No. of patients still at risk Censoring Times Everolimus (n/n = 42/205) Placebo (n/n = 28/97) Months 205 195 184 179 172 170 158 143 100 59 31 5 0 97 94 86 80 75 70 67 61 42 21 13 5 0 *P-value boundary for significance = 0.0002. P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. NS, not significant. Yao JC et al. Lancet 2016;387:968-977.

RADIANT-4 : GI Subgroup Study Design Patients with welldifferentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N = 302) Absence of active or any history of carcinoid syndrome Pathologically confirmed advanced disease Enrolled within 6 months from radiologic progression R A N D O M I Z E 2:1 Everolimus 10 mg/day N = 205 Placebo N = 97 Treated until PD, intolerable AE, or consent withdrawal Gastrointestinal N = 118 Unknown primary N = 23 Gastrointestinal N = 57 Unknown primary N = 13 Endpoints: Primary: PFS (central) Key Secondary: OS Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK Core study stratified by: Prior SSA treatment (yes vs. no) Tumor origin (stratum A vs. B)* WHO PS (0 vs. 1) *Based on prognostic level, grouped as: Stratum A (better prognosis) - appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worse prognosis) - lung, stomach, rectum, and colon except caecum. Crossover to open label everolimus after progression in the placebo arm was not allowed prior to the primary analysis. Singh S et al. 2016 European Neuroendocrine Tumor Society (ENETS), Barcelona, Spain. Abstract L20

Probability of progression-free survival (%) PFS by Central Review Probability of progression-free survival (%) Everolimus improved median PFS in both the GI and unknown primary subgroups 100 90 80 70 60 50 40 30 20 10 0 Everolimus Placebo GI Subgroup Kaplan-Meier medians Everolimus: 13.1 mo (95% CI, 9.2-17.3) Placebo: 5.4 mo (95% CI, 3.6-9.3) HR: 0.56 (95% CI, 0.37; 0.84) 1 Censoring Times Everolimus (n/n = 59/118) Placebo (n/n = 39/57) 0 2 4 6 8 10 12 15 18 21 24 27 30 Time (Months) No. of patients still at risk 118 99 82 71 60 49 41 33 16 8 3 0 0 57 40 27 21 16 14 12 10 8 5 4 1 0 HR values presented are based on unstratified Cox regression analysis. 100 90 80 70 60 50 40 30 20 10 0 Everolimus Placebo Unknown Primary Subgroup Kaplan-Meier medians Everolimus: 13.6 mo (95% CI, 4.1-NA) Placebo: 7.5 mo (95% CI, 1.9-18.5) HR: 0.60 (95% CI, 0.24; 1.51) 1 Censoring Times Everolimus (n/n = 11/23) Placebo (n/n = 8/13) 0 2 4 6 8 10 12 15 18 21 24 27 30 Time (Months) No. of patients still at risk 23 18 15 13 10 10 8 6 2 1 0 0 0 13 10 5 4 3 2 2 2 2 1 1 0 0 HR values presented are based on unstratified Cox regression analysis. 1. Yao JC et al. Lancet 2016;387:968-977. Singh S et al. 2016 European Neuroendocrine Tumor Society (ENETS), Barcelona, Spain. Abstract L20 54

Probability of progression-free survival (%) PFS: Midgut vs Non-midgut Subgroup Probability of progression-free survival (%) 100 90 80 70 60 50 40 30 20 10 0 Everolimus Placebo Midgut 29% reduction in the relative risk of progression or death and a median PFS Δ6.4 months with everolimus vs placebo Censoring Times Everolimus (n/n = 33/80) Placebo (n/n = 20/35) Kaplan-Meier medians Everolimus: 17.3 mo (95% CI, 11.2-21.9) Placebo: 10.9 mo (95% CI, 5.1-19.4) HR: 0.71 (95% CI, 0.40-1.26) 0 2 4 6 8 10 12 15 18 21 24 27 30 Time (Months) No. of patients still at risk 80 66 58 52 45 38 32 27 11 6 3 0 0 35 31 22 18 15 13 11 9 7 5 4 1 0 HR values presented are based on unstratified Cox regression analysis. Duodenum (n=10) is included under midgut subgroup assuming they were located distally. Both arms received best supportive care. 100 90 80 70 60 50 40 30 20 10 0 Everolimus Placebo Non-midgut 73% reduction in the relative risk of progression or death and a median PFS Δ6.2 months with everolimus vs placebo Kaplan-Meier medians Everolimus: 8.1 mo (95% CI, 5.5-11.2) Placebo: 1.9 mo (95% CI, 1.8-3.6) HR: 0.27 (95% CI, 0.15-0.51) Censoring Times Everolimus (n/n = 26/38) Placebo (n/n = 19/22) 0 2 4 6 8 10 12 15 18 21 24 27 30 Time (Months) No. of patients still at risk 38 33 24 19 15 11 9 6 5 2 0 0 0 22 9 5 3 1 1 1 1 1 0 0 0 0 HR values presented are based on unstratified Cox regression analysis. Both arms received best supportive care. Midgut NET included primary tumors originating in the ileum, jejunum, caecum, duodenum, appendix, and small intestine (ileum and jejunum) while the nonmidgut NET included primary tumors originating from the stomach, colon, and rectum Singh S et al. 2016 European Neuroendocrine Tumor Society (ENETS), Barcelona, Spain. Abstract L20 55

Probability of progression-free survival (%) PFS: Prior-SSA vs Non-SSA Subgroup Probability of progression-free survival (%) Prior-SSA 46% reduction in the relative risk of progression or death with a median PFS Δ6.7 months with everolimus vs placebo No Prior-SSA 40% reduction in the relative risk of progression or death with a median PFS Δ9.1 months with everolimus vs placebo 100 90 80 70 Kaplan-Meier medians Everolimus: 11.2 mo (95% CI, 9.2-17.3) Placebo: 4.5 mo (95% CI, 3.6-9.0) HR: 0.54 (95% CI, 0.32-0.89) 100 90 80 70 Kaplan-Meier medians Everolimus: 16.6 mo (95% CI, 9.2-20.9) Placebo: 7.5 mo (95% CI,3.1-18.5) HR: 0.60 (95% CI, 0.34-1.05) 60 60 50 50 40 40 30 20 10 0 Censoring Times Everolimus (n/n = 37/77) Placebo (n/n = 26/38) 30 20 10 0 Censoring Times Everolimus (n/n = 33/64) Placebo (n/n = 21/32) 0 2 4 6 8 10 12 15 18 21 24 27 30 0 2 4 6 8 10 12 15 18 21 24 27 30 No. of patients still at risk Time (Months) No. of patients still at risk Time (Months) Everolimus 77 61 47 38 33 30 24 18 10 6 3 0 0 Everolimus 64 56 50 46 37 29 25 21 8 3 0 0 0 Placebo 38 28 16 12 8 6 6 6 5 4 3 0 0 Placebo 32 22 16 13 11 10 8 6 5 2 2 1 0 HR values presented are based on unstratified Cox regression analysis. *Prior- SSA analysis was based on case report forms. Both arms received best supportive care. HR values presented are based on unstratified Cox regression analysis. Both arms received best supportive care. SSA was mostly administered for tumor control Singh S et al. 2016 European Neuroendocrine Tumor Society (ENETS), Barcelona, Spain. Abstract L20 56

Conclusion In this post-hoc analysis of the RADIANT-4 study, everolimus showed clinically meaningful PFS benefit in patients with GI NET and NET of unknown primary Everolimus improved median PFS in both midgut and non-midgut population within the GI subgroup Everolimus showed a 40-46% reduction in relative risk of progression or death, in patients without or with prior SSA therapy Safety profile for everolimus is consistent with previous findings and no new safety signals were observed Everolimus presents a new standard treatment option in patients with advanced progressive nonfunctional NET of GI or unknown primary Singh S et al. 2016 European Neuroendocrine Tumor Society (ENETS), Barcelona, Spain. Abstract L20 57

ECC 2015; Late-breaker abstract 6LBA NETTER-1: study design

ECC 2015; Late-breaker abstract 6LBA NETTER-1: 177 Lu-Dotatate resulted in significantly longer PFS By this analysis, 90 progression or death events occurred, imbalanced between the two groups: 177 Lu-Dotatate = 23 Octreotide LAR 60 mg = 67 HR=0.209, 95% CI 0.129 0.338, p<0.0001

ECC 2015; Late-breaker abstract 6LBA NETTER-1: longer OS was favoured with 177 Lu-Dotatate treatment but wasn t significant (level of significance p< 0.000085)

ECC 2015; Late-breaker abstract 6LBA NETTER-1: 177 Lu-Dotatate appeared to be associated with more TRAEs

Stage IV NETs G3 (WHO) Αντι-νεοπλασματική θεραπεία - Χημειοθεραπεία Clinical Evidence based on Ph II studies

ΕΝΔΟΣΚΟΠΙΚΗ/ΧΕΙΡΟΥΡΓΙΚΗ ΘΕΡΑΠΕΙΑ GEP- NETs Ριζική θεραπεία πρωτοπαθούς +/- μετα νόσος ήπατος Debulking θεραπεία 1.Λειτουργικοί όγκοι που δεν ελέγχονται από άλλη θεραπεία 2. υπολειμματική νόσος Παρηγοριτική θεραπεία απόφραξη-bypasses

Median Survival: 8.5y Median Survival (non cytoreduction): 7.9y vs 11.5y 5-y Survival 75%

Συμπεράσματα Αντιμετώπιση των ασθενών σε ειδικά κέντρα (Centers Excellence) από ομάδα συναφών ιατρικών ειδικοτήτων. Σημαντικοί παράμετροι θεραπείας: Εντόπιση πρωτοπαθούς εστίας. Πρόοδος νόσου ή σταθεροποιημένη νόσος? Στάδιο και διαφοροποίηση της νόσου? Καλά οργανωμένες κ ελεγχόμενες μελέτες (phase III or non-inferiority) trials Συνδυασμός θεραπειών-μεθόδων.