Επίπησζε GEP-NETs απμάλεηαη (Gastroenteropancreatic Neuroendocrine Tumors)

Randomized, Phase III Trial of Everolimus + Octreotide LAR vs. Placebo + Octreotide LAR in Patients with Advanced Neuroendocrine Tumors (NET) (RADIANT-2) Marianne Pavel 1, John Hainsworth 2, Eric Baudin 3, Peeters 4, Dieter Hoersch 5, Lowell Anthony 6, Sakina Hoosen 7, Jessica St Peter 7, Valentine Jehl 8, and James Yao 9 for the RADIANT-2 Study Group 1 Charité-Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, Germany; 2 Sarah Cannon Cancer Center, Nashville, TN, USA; 3 Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave Roussy, Villejuif, France; 4 Department of Oncology, Antwerp University Hospital, Edegem, Belgium; 5 Klinik für Innere Medizin, Gastroenterologie und Endokrinologie, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; 6 Ochsner Kenner Medical Center, Kenner, LA, USA; 7 Novartis Oncology, Florham Park, NJ, USA; 8 Novartis Pharma, Basel, Switzerland ; 9 M. D. Anderson Cancer Center, Houston, TX, USA

Incidence per 100,000 - NETs Incidence per 100,000 All malignant neoplasms Επίπησζε GEP-NETs απμάλεηαη (Gastroenteropancreatic Neuroendocrine Tumors) 6.00 5.00 Όλα κακοήθη νεοπλάςματα 600 500 4.00 400 3.00 300 2.00 200 1.00 Νευροενδοκρινείσ όγκοι 100 0.00 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1980 1979 1978 1977 1976 1975 1974 1973 0 Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

Ο αζζελήο κε GEP NET όγθν κπνξεί λα εκθαλίζεη Flushing Εθίδρφζη Καρδιο-αναπνεσζηική καηέρριυη Υπόηαζη Εξάνθημα Σακτ. Διαβήηης Απίζτναζη Μσοπάθεια Σοβαπή διάπποια Αθσδάηφζη Υποκαλιαιμία Υποτλφρσδρία Υπογλςκαιμία Πεπτικό έλκορ

Τπνεθηίκεζε ζπκπησκάησλ θαζπζηεξεκέλε δηάγλσζε Localized Distant Regional Flushing Χσξίο δηάξξνηεο Δπάγεηαη αιθνόι Γηάξξνηα Ιδηαίηεξα λπθηεξηλέο 27% 24% 50% Βξνγρόζπαζκν Δπεξέζηζην έληεξν Μεηεσξηζκόο Yao JC et al. J Clin Oncol. 2008;26:3063-3072.

GEP-NETs δηαγηγλώζθνληαη ζπλήζσο θαζπζηεξεκέλα Αςαφή κοιλιακά ενοχλήματα Θάνατοσ Διάρροια Flushing Ανάπτυξη μεταςτάςεων Πρωτοπαθήσ όγκοσ Χρόνοσ Vinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.

Πρόοδοσ νόςου Μέρξηο ζήκεξνλ πεξηνξηζκέλεο ζεξαπεπηηθέο επηινγέο pnet Λειτουργικοί Μη Λειτουργικοί Octreotide LAR + χημειοθεραπεία Χημειοθεραπεία ΗΑΕ PPRT Καρκινοειδείσ όγκοι Καρκινοειδζσ Σφνδρομο (ΚΣ) Midgut Χωρίσ ΚΣ Octreotide LAR? ΙNF PROMID Πειραματικά φάρμακα (Aπουςία εγκεκριμζνων θεραπειών) Non-midgut Χωρίσ ςφνδρομο No standard LAR = long-acting release; pnet = pancreatic NET

Επηηαθηηθή αλάγθε εμεύξεζεο θαξκάθσλ γηα επίηεπμε ειέγρνπ λόζνπ Eπηβίσζε αζζελώλ NET κε κεηαζηάζεηο (1988-2004) Carcinoid Pancreatic NET Γηάκεζε επηβίσζε Καξθηλνεηδείο όγθνη 43 κήλεο pnet 27 κήλεο Yao JC et al. J Clin Oncol. 2008;26:3063-3072. Πεξηνξηζκέλεο επηινγέο Καξθηλνεηδείο Eγθεθξηκέλα θάξκαθα (PROMID) Sandostatin LAR (Midgut) pnet Streptozocin εγθεθξηκέλε αιιά ζεκαληηθή ηνμηθόηεηα Έιιεηςε consensus γηα standard treatment γηα έιεγρν επέθηαζεο όγθνπ

Tuberous Sclerosis gene function (TSC1 and TSC2) Peutz-Jeghers Syndrome PAR1 LKB1 STRAD AMPK mtor Constitutive Activation Akt Rheb PDK1 PDK2 Tuberous Sclerosis PIP 3 TSC1 TSC2 PIP 2 PI3K IRS 1 Wnt Cowden syndrome BRRS PTEN Frizzled GSK3 Axin APC Loss of Cell Polarity 4EBP1 Raf Ras BMP -Cat S6K1 eif4e MAPK HIF TCF CREB? Mitf,.. Unregulated cell growth and protein biosynthesis VEGF, TGF PDGF Melanocytic hyperplasia and altered migration GI ISC & endocrine cell dysregulation Bauer AJ & CA Stratakis. J Med Genet. 2006

Αλαζηνιή MTOR Eπξήκαηα θιηληθή πξάμε Tuberous sclerosis (TS) TSC1, TSC2 mtor Γελεηηθέο κεηαιιάμεηο TSC2 ηδηνζπζηαηηθή ελεξγνπνίεζε mtor TS ζπλδπάδεηαη κε θαθνήζε παγθξεαηηθά ελδνθξηληθά λενπιάζκαηα

Eπξήκαηα θιηληθή πξάμε Nεπξντλσκάησζε NF1 ξπζκίδεη mtor κέζσ TSC2 NF1 ηδηνζπζηαηηθή ελεξγνπνίεζε mtor NεπξνΪλσκάησζε θαξθηλνεηδείο όγθνπο θύκαηνο Vater, δσδεθαδάθηπιν Johannessen et al, Proc Natl Acad Sci 2005;102(24):8573-8.

θεπηηθό ρξήζεο ζπλδπαζκνύ Everolimus θαη Octreotide LAR ζε αζζελείο κε λεπξνελδνθξηλείο όγθνπο mtor θεληξηθόο ξπζκηζηήο θπηηαξηθνύ πνιιαπιαζηαζκνύ, κεηαβνιηζκνύ, αγγεηνγέλεζεο 1-3 GEP-NET εκθαλίδνπλ γελεηηθέο ηξνπνπνηήζεηο ελεξγνπνίεζε mtor 2,3 IGF-1 IGF-1R PTEN IGF-1 IGF-1R VEGFR VEGF signaling Everolimus mtor 3 Octreotide downregulates IGF-1, ελεξγνπνηεηή PI3K/AKT/mTOR κνλνπαηηνύ 4 Survival mtor inhibitor X Growth and proliferation mtor TSC1/2 X X X NF1 Metabolism VHL Angiogenesis Everolimus + octreotide LAR απνηειεζκαηηθόηεηα θάζε II trial 5 1. O Reilly T, McSheehy PM. Transl Oncol. 2010;3(2):65-79. 2. Meric-Bernstam F, Gonzalez-Angulo AM. J Clin Oncol. 2009;27:2278-2287. 3. Faivre S, Kroemer G, Raymond E. Nat Rev Drug Disc. 2006;5:671-688. 4. Susini C, Buscail L. Ann Oncol. 2006;17:1733-1742. 5. Yao JC, Phan AT, Chang DZ, et al. J Clin Oncol. 2008;26:4311-4318.

Αναστολείς mtor χρησιμοποιήθηκαν σε κλινικές μελέτες GEP-NET Σθεύαζκα Target & mechanism Μειέηε RR Reference - + Temsirolimus (CCI-779) Everolimus (RAD001) mtor Protein kinase inhibitor mtor Protein kinase inhibitor Φάζε II Καξθηλνεηδείο pnet Φάζε II Καξθηλνεηδείο pnet 4,8 % 6,7 % 13 % 27 % (Duran et al., 2006) (Yao et al., 2007)

Φάζε 2 κειέηε ζε αζζελείο κε εθηεηακέλνπο GEP- NET Single-arm θαζε 2 Yςεινύ ή ελδηάκεζνπ βαζκνύ δηαθνξνπνίεζεο NET πξόνδν λόζνπ Καξθηλνεηδείο (n=30) ΔΠΟ (n=30) RAD001 doses 5 mg daily (αζζελείο 1-30) 10 mg daily (αζζελείο 31-60) RAD001 5 or 10 mg PO ημζρα + Sandostatin LAR 30 mg IM ανά 28 ημζρεσ 0 4 8 12 CT/MRI Εβδομάδεσ CT/MRI Καταληκτικά ςημεία Πρωταρχικό καταληκτικό ςημείο: απάντηςη θεραπεία αντικειμενικά κριτήρια (RECIST) Δευτερεφων καταληκτικό ςημείο : PFS, βιοχημική απάντηςη, αςφάλεια

MDACC: Everolimus + Octreotide LAR (Απάληεζε Response) Per protocol Σφνολο N = 60 Καρκινοειδείσ n = 30 Παγκρεατικοί ενδοκρινείσ n = 30 PR 13 (22%) 5 (17%) 8 (27%) SD 42 (70%) 24 (80%) 18 (60%) PD 5 (8%) 1 (3%) 4 (13%) PFS (median) 60 wks 63 wks 50 wks ITT RR: 20% MDACC = M. D. Anderson Cancer Center; RR = response rate Yao JC et al. J Clin Oncol. 2008;26:4311-4318.

Απνηειεζκαηηθόηεο PFS Όλοι αςθενείσ Ομάδεσ αςθενών 6- και 12 - μήνεσ PFS 86% και 59% 6- και 12- μήνεσ PFS 86% και 69% καρκινοειδείσ 73% και 48% παγκρεατικοφσ ενδοκρινείσ όγκουσ (P=0.46) Yao et al. J Clin Oncol. 2008;26:4311-4318.

Ομάδεσ αςθενών Disease Status P Cox HM, RAD001 10mg and progression at study entry were associated with superior and shorter PFS respectively (not sufficiently powered) PFS 68% (6ms) 40% (12ms) PD vs. 100% and 81% SD at study entry (P=0.01) Yao et al. J Clin Oncol. 2008;26:4311-4318.

RAD001 Tumor Response: Καξθηλνεηδήο όγθνο Baseline 12 weeks Yao et al. ASCO 2006 GI Cancer Symposium. Abstract 178.

RADIANT-1: Study Design Eθηεηακέλνη παγθξεαηηθνί NET κε δηαπηζησκέλε πξόνδν λόζνπ κε βάζε θξηηήξηα RECIST κεηά ρνξήγεζε ρεκεηνζεξαπείαο Stratum 1: Χσξίο ιήςε octreotide LAR 60d πξo εηζαγσγήο - everolimus 10 mg/d Stratum 2: Octreotide LAR 3 κήλεο πξν εηζαγσγήο - everolimus 10 mg/d + octreotide LAR ( 30 mg, q28d) S C R E E N Stratum 1 n = 115 Stratum 2 n = 45 Everolimus Everolimus + octreotide LAR Πρωταρχικό καταληκτικό ςημείο RR stratum 1 Δευτερεφων καταληκτικό ςημείο RR stratum 2 Response (διάρκεια) Αςφάλεια PFS Επιβίωςη Θεραπεία μζχρισ πρόοδο νόςου; CT ή MRI baseline & 3 μήνεσ PK = pharmacokinetics; RECIST = Response Evaluation Criteria In Solid Tumors Yao JC et al. J Clin Oncol. 2010;28:69-76.

RADIANT-1: Επίηεπμε θαιύηεξνπ απνηειέζκαηνο από αξρηθή εθηίκεζε Central Radiology Review Stratum 1: Everolimus (n = 115) Central radiology ITT, n (%) PR 11 (9.6) SD 78 (67.8) Κλινική οφζλεια (PR + SD) 89 (77.4) PD 16 (13.9) Unknown 10 (8.7) Stratum 2: Everolimus + Octreotide LAR (n = 45) Central radiology ITT, n (%) PR 2 (4.4) SD 36 (80.0) Κλινική οφζλεια (PR + SD) 38 (84.4) PD 0 (0.0) Unknown 7 (15.6) Yao JC et al. J Clin Oncol. 2010;28:69-76.

Probability (%) Probability (%) RADIANT-1 PFS Central Review Everolimus 100 Everolimus + octreotide LAR 100 80 n = 115 80 n = 45 60 40 20 0 Median PFS = 9.7 mo 0 2 4 6 8 10 12 14 16 18 20 22 24 Time, mo Patients at risk 115 111 81 58 54 36 25 15 12 5 3 3 1 0 26 60 40 20 0 Patients at risk Median PFS = 16.7 mo 0 2 4 6 8 10 12 14 16 18 20 22 Time, mo 45 39 32 22 21 19 14 10 8 3 3 1 24 0 Yao JC et al. J Clin Oncol. 2010;28:69-76.

Pivotal Phase 3 Trials with Everolimus in NETs Advanced carcinoid with syndrome in progression (N = 429) R Lancet, 2011 (378):2011 Octreotide LAR + Everolimus Octreotide LAR + placebo Advanced pnet in progression (N = 410) R NEJM, 2011 (364):514 Best supportive care + everolimus* Best supportive care + placebo* *Octreotide LAR included as best supportive care.

RADIANT-2 Study Design Φασης III Double Blind Placebo Controlled Trial Αζζελείο κε NET θαη ηζηνξηθό ζπκπησκάησλ ελδεηθηηθώλ θαξθηλνεηδνύο ζπλδξόκνπ, N = 429 R A N D O M I Z E 1:1 Everolimus 10 mg/d + Octreotide LAR 30 mg/28 εκέξεο n = 216 Crossover Placebo + Octreotide LAR 30 mg/28 εκέξεο n = 213 Θεξαπεία κέρξηο πξόνδν λόζνπ Multi-phasic CT ή MRI κάθε 12 εβδομάδες Πξσηαξρηθό θαηαιεθηηθό ζεκείν: PFS (RECIST) Έληαμε 01.2007 03.2008 Δεπηεξεύσλ θαηαιεθηηθό ζεκείν: Απάληεζε ζεξαπεία θνξηίνπ όγθνπ, OS, biomarkers, αζθάιεηα

Πξνϋπνζέζεηο επηινγήο αζζελώλ G1 θαη G2 GEP-NET (θαιήο δηαθνξνπνίεζεο, ρακειήοκέζεο θαθνήζεηαο θαξθηλνεηδείο όγθνη) Δπηβεβαησκέλε πξόνδνο λόζνπ ηειεπηαίνπο 12 κήλεο Μεηξήζηκε λόζνο κε θξηηήξηα RECIST Multi-phasic computed tomography (CT) scan ή MRI Ιζηνξηθό παξνπζίαο ζπκπησκάησλ ελδεηθηηθώλ θαξθηλνεηδνύο ζπλδξόκνπ Δπηηξεπηή απνπζία ζπκπησκάησλ θαηά ηελ πεξίνδν ηεο επηινγήο Δπηηξεπηή πξνεγνύκελε ζεξαπεία λόζνπ WHO PS < 2, επαξθείο αηκαηνινγηθνί θαη βηνρεκηθνί παξάκεηξνη, κεηαβνιηθό πξνθίι

RADIANT-2 Εθηίκεζε απνηειεζκαηηθόηεηαο Πξσηαξρηθό θαηαιεθηηθό ζεκείν: Progression-free survival (PFS) κεηά εθηίκεζε από αλεμάξηεηε αξρή* (RECIST 1.0) Δπίπεδν ζεκαληηθόηεηαο: One-sided log-rank, P = 0.0246 287 PFS ζπκβάκαηα απαξαίηεηα γηα ηζρύ 92.2% [90 εβδ, 10% απώιεηα πεξηζηαηηθώλ 390 Pre-specified IPCW analysis γηα αλάδεημε bias ιόγσ crossover θαη informative censoring Γεπηεξεύνληα θαηαιεθηηθά ζεκεία: OS, αζθάιεηα, tumour response, biomarkers * Independent adjudicated central review committee έσο 2 έηε

Δηάκεζε ειηθία έηε (δηαθύκαλζε) Everolimus + Oct LAR N = 216, % Placebo + Oct LAR N = 213, % 60 (22-83) 60 (27-81) Άξξελεο 45 58 Θήιεα 55 42 WHO Performance Status 0 55 66 1 / 2* 39 / 6 29 / 5 Πξσηνπαζήο εληόπηζε Επηκέξνπο ραξαθηεξηζηηθά νκάδσλ Λεπηό έληεξν 51% 53% Πλεύκνλαο* 15% 5% Κόινλ 7% 7% Πάγθξεαο 5% 7% Ήπαξ 3% 5% *One missing PS in placebo arm Oct LAR= Octreotide LAR *Statistically significant for imbalance, P < 0.05

Πξνεγνύκελεο ρνξεγεζείζεο ζεξαπείεο Everolimus + Oct LAR N = 216 n (%) Placebo + Oct LAR N = 213 n (%) Μαθξάο δηάξθεηαο SSA 173 (80.1) 166 (77.9) Λνηπέο ζεξαπείεο έλαληη όγθνπ 99 (45.8) 82 (38.5) Χεκεηνζεξαπεία* 75 (34.7) 55 (25.8) Αλνζνζεξαπεία 27 (12.5) 20 (9.4) Σηνρεπκέλε ζεξαπεία 15 (6.9) 16 (7.5) Άιιεο ζεξαπείεο 21 (9.7) 28 (13.1) Grade G1-2 77%, G2 18% G1-2 82%, G2 14% *Statistically significant, p < 0.05 Oct LAR = Octreotide LAR

Υαξαθηεξηζηηθά αζζελώλ Everolimus + Oct LAR N = 216, n (%) From everolimus/placebo double blind trial prior to data cut off date of April 2,2010 Oct LAR = Octreotide LAR Placebo + Oct LAR N = 213, n (%) πλέρηζε ζεξαπείαο 37 (17.1) 34 (16.0) Αζζελείο πνπ δηέθνςαλ 179 (82.9) 179 (84.0) Πξόνδνο λόζνπ 95 (44.0) 146 (68.5) Αλεπηζύκεηεο ελέξγεηεο 57 (26.4) 14 (6.6) Απόζπξζε ζπγθαηάζεζεο 17 (7.9) 11 (5.2) Θάλαηνο 6 (2.8) 2 (0.9) Παξαβίαζε πξσηνθόιινπ 3 (1.4) 4 (1.9) Νέα αληηλενπιαζκαηηθή ζεξαπεία 1 (0.5) 1 (0.5) Διιεηπή ζηνηρεία παξαθνινύζεζεο 0 1 (0.5) Δηάξθεηα ζεξαπείαο (εβδνκάδεο) Γηάκεζνο ηηκή 37 37 Δύξνο 1-163 0-152 Crossover ζε everolimus ---- 123

Percentage event-free PFS ηoπηθήο αμηνιόγεζεο 100 80 60 Kaplan-Meier median PFS Everolimus + Octreotide LAR: 12.0 κήλεο Placebo + Octreotide LAR: 8.6 κήλεο Hazard ratio = 0.78; 95% CI [0.62-0.98] P-value = 0.018 No. Αζζελώλ ζε θίλδπλν E + O P + O 40 20 0 216 213 199 201 Σπλνιηθά ζπκβάκαηα = 284 Censoring times E + O (n/n = 128/216) P + O (n/n = 156/213) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 167 159 129 121 119 114 100 92 81 75 Χξόλνο (κήλεο) 74 72 68 64 62 56 51 50 40 41 32 27 24 21 18 11 11 10 4 4 2 1 1 0 0 0 P-value is obtained from the one-sided log rank test Hazard ratio is obtained from unadjusted Cox model E + O = Everolimus + Octreotide LAR P + O = Placebo + Octreotide LAR

Percentage event-free PFS θεληξηθήο αμηνιόγεζεο* 100 80 60 Kaplan-Meier median PFS Everolimus + Octreotide LAR: 16.4 κήλεο Placebo + Octreotide LAR: 11.3 κήλεο Hazard ratio = 0.77; 95% CI [0.59-1.00] P-value = 0.026 Αξηζκόο αζζελώλ ζε θίλδπλν E + O P + O 40 20 0 216 213 202 202 Σύλνιν ζπκβακάησλ = 223 Censoring times E + O (n/n = 103/216) P + O (n/n = 120/213) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 167 155 129 117 120 106 102 84 81 72 Χξόλνο (κήλεο) 69 65 63 57 56 50 50 42 42 35 33 24 22 18 17 11 11 9 4 3 1 1 1 0 0 0 * Independent adjudicated central review committee P-value is obtained from the one-sided log rank test Hazard ratio is obtained from unadjusted Cox model E + O = Everolimus + Octreotide LAR P + O = Placebo + Octreotide LAR

Κεληξηθή αμηνιόγεζε Σνπηθή αμηνιόγεζε Κεληξηθή Σνπηθή PFS extension 11.3 16.4 months 8.6 12 months HR / risk reduction 0.77 / 23% 0.78 / 22% total events 223 284 p value 0.026 0.018

Inverse Probability of Censoring Weights Analysis (IPCW) Pre-specified in study Recognized methodology to adjust for different censoring patterns, loss of power and imbalance in baseline characteristics Established and validated analysis applied to other large Phase III trials by cooperative groups (BIG1-98 1, ACTG-021(HIV) 2 ) IPCW adjusted PFS HR = 0.60; 95% CI [0.44-0.84]; P = 0.0014 in favor of everolimus + octreotide LAR 1. Mouridsen, H et al. NEJM 2009 361(8) :766-776 ; 2. Robins JM et al. Biometrics. 2000; 56(3):779-88

Subgroup PFS Analysis Τπννκάδεο (N) Favors E + O Favors P + O Median PFS (mos.) HR E + O P + O Κεληξηθή αμηνιόγεζε *(429) 0.77 16.4 11.3 Σνπηθή αμηνιόγεζε (429) 0.78 12.0 8.6 Οκάδεο αζζελώλ <65 έηε (286) 0.78 19.2 13.0 65 έηε (143) 0.75 13.9 11.0 Φύιν Άξξελ (221) 0.85 13.7 13.0 Θήιπ (208) 0.73 17.1 11.1 WHO Performance Status WHO = 0 (251) 0.67 19.3 13.6 WHO > 0 (176) 0.81 13.8 8.3 Tumour histology grade Καιή δηαθ.(341) 0.74 18.3 13.0 Μέηξηα δηαθ. (68) 0.82 13.7 7.5 Πξσηνπαζήο εζηία Λεπηό έληεξν (224) 0.77 18.6 14.0 Πλεύκσλ (44) 0.72 13.6 5.6 Κόινλ (28) 0.39 29.9 13.0 Άιιε (132) 0.77 14.2 11.0 Πξνεγνύκελε ζεξαπεία κε SSA ΝΑΙ (339) 0.81 14.3 11.1 ΟΧΙ (90) 0.63 25.2 13.6 Πξνεγνύκελε ρεκεηνζεξαπεία ΝΑΙ (130) 0.70 13.9 8.7 ΟΧΙ (299) 0.78 19.2 12.0 *Independent adjudicated central review HR = Everolimus + Octreotide/Placebo + Octreotide Unstratified Cox model was used to obtain hazard ratio 0 0.4 0.8 1 1.4 Hazard Ratio E + O = Everolimus + Octreotide LAR P + O = Placebo + Octreotide LAR

Fold change from baseline Fold change from baseline Αιιαγέο επηπέδσλ νξνύ CgA θαη 5-HIAA νύξσλ 24ώξνπ θαηά δηάξθεηα ζεξαπείαο Serum CgA Concentrations Urinary 5-HIAA Concentrations 2.0 1.8 Everolimus + octreotide LAR Placebo + octreotide LAR 2.0 1.8 Everolimus + octreotide LAR Placebo + octreotide LAR 1.6 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 Cycle: 0 2 3 4 5 6 7 8 9 10 11 12 Cycle: 0.0 0 2 3 4 5 6 7 8 9 10 11 12 *Least-square estimates of mean fold change and 95% CI obtained using a mixed model, including terms for baseline value, treatment, time, and interaction between time and treatment. Only patients with elevated levels at baseline (>1 x ULN) were included. CgA P value for main treatment effect = 0.004. 5-HIAA P value for main treatment effect < 0.001. Everolimus + octreotide LAR πξνθάιεζε ηαρεία θαη δηαξθή ειάηησζε CgA (P value = 0.004) 24-hour urinary 5- HIAA νύξσλ 24-ώξνπ (P value < 0.001) versus ΜΗ ΑΛΛΑΓΗ κε placebo + octreotide LAR After one treatment cycle, the least square estimate for the ratio of the fold change from baseline in everolimus + octreotide LAR versus placebo + octreotide LAR was 0.85 (95% confidence interval [CI], 0.70-1.02) for CgA and 0.84 (95% CI, 0.71-1.00) for 5-HIAA Baudin E, Castellano D, Wolin E, et al. WCGI 2011, Barcelona, Spain. 35

πλνιηθή επηβίσζε (Overall Survival, OS) 123 αζζελείο νκάδαο placebo crossed over κε ηελ πξόνδν λόζνπ 185 ζάλαηνη δηαθνπή κειέηεο; Τειηθή overall survival analysis 252 ζπκβάκαηα Interim survival analysis no statistical difference overall survival, HR = 1.22; 95% CI [0.91-1.62]; P = 0.908 Kaplan-Meier estimates [95% CI] at: Everolimus + Octreotide LAR N = 216 Placebo + Octreotide LAR N = 213 6 months 91.1 [86.4-94.2] 92.4 [87.9-95.3] 12 months 80.9 [74.9-85.6] 81.8 [75.8-86.4] 18 months 70.6 [63.9-76.3] 73.5 [66.9-79.0] 24 months 57.1 [49.9-63.6] 63.3 [56.2-69.5] Data cut-off: April 2, 2010

Αλεπηζύκεηεο ελέξγεηεο ζρεηηδόκελεο κε ζεξαπεία πκβάκαηα >10% Everolimus + Octreotide LAR n = 215 Placebo + Octreotide LAR n = 211 All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) ηνκαηίηηο* 62 7 14 0 Εμάλζεκα 37 1 12 0 Καηαβνιή 31 7 23 3 Δηάξξνηα 27 6 16 2 Nαπηία 20 1 16 1 Λνηκώμεηο* 20 5 6 1 Δπζγεπζία 17 1 3 0 Aλαηκία 15 1 5 0 Απώιεηα βάξνπο 15 1 3 0 Θξνκβνθπηνπελία 14 5 0 0 Ειάηησζε όξεμεο 14 0 6 0 Πεξηθεξηθό νίδεκα 13 0 3 0 Τπεξγιπθαηκία 12 5 2 1 Δύζπλνηα 12 2 1 0 Πλεπκνληθά ζπκβάκαηα* 12 2 0 0 Έκεηνη 11 1 5 1 Κλεζκόο 11 0 4 0 Aδπλακία 10 1 7 1 *Related toxicities grouped for calculations

ΤΜΠΕΡΑΜΑΣΑ Everolimus + octreotide LAR επηκήθπλζε ηνπ δηάκεζνπ PFS 5.1 κήλα (HR = 0.77; P = 0.026) ρσξίο επίηεπμε prespecified statistical significance (P = 0.0246) Τνπηθή αλάιπζε ζπλεγνξεί ππέξ ηεο δξαζηηθόηεηαο everolimus + octreotide LAR κε ζεκαληηθό HR of 0.78 (P = 0.018) Pre-specified statistical analysis (IPCW) adjusting for different censoring patterns, loss of power and baseline imbalances demonstrates a consistent benefit (HR = 0.60) Everolimus + octreotide LAR εκθαλίδεη δξαζηηθόηεηα ζε θαξθηλνεηδείο όγθνπο κε πξνέιεπζε από δηαθνξεηηθέο πξσηνπαζείο εζηίεο Everolimus + octreotide LAR αζθαιήο ζεξαπεία

RADIANT-2, ΤΜΠΕΡΑΜΑΣΑ Σπλδπαζκόο Everolimus & octreotide LAR ζεκαληηθή επηκήθπλζε PFS θιηληθά Τα επξήκαηα απηά καδί κε ηα αληίζηνηρα ηεο RADIANT-3 trial, ππνζηεξίδνπλ ηε δξαζηηθόηεηα everolimus ζε αζζελείο κε εθηεηακέλνπο GEP-NET

mtor Signaling Pathways Receptor Tyrosine Kinase Nutrients & Metabolites IRS-1 P PI3K P Grb SOS RAS AKT TSC1/2 Rheb mtorc1 Protein Synthesis Everolimus p70s6k P 4EBP1 P eif4e Glut 1 Metabolism HIF-1α VEGF, PDGF-β Angiogenesis Cyclin D, p27 Growth & Proliferation

Aπεηθνληζηηθέο κέζνδνη GEP όγθσλ

Anatomic CT and Indium-111 Pentetreotide Scintigraphy Imaging studies property of James Yao, MD.

Neuroendocrine Tumor Register

GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS (GEP NET) REGISTRY 20 πεοιζηαηικά/ 1 000 000 πληθρζμξύ έηξπ (γρμαίκεπ > άμδοεπ); Εονωπαϊθόξ πιεζοζμόξ: 761 million 15 000 κέμη GEP NET αζθεμείπ αμά έηξπ. 84/ 1 000 000 (autopsy) Ευρωπαϊκόσ πληθυςμόσ: 761 million 64 000 νέοι GEP NET αςθενείσ ανά ζτοσ. Σκξπόπ registry βειηίωζε θαηαγναθήξ δεδμμέκωκ κόζμο δεμημονγία ζοζηήμαημξ quality-management γηα ηε δηάγκωζε θαη ζεναπεία NET οημζέηεζε θαη εθανμμγή βαζηθήξ πμηόηεηαξ ακηημεηώπηζεξ αζζεκώκ με NET μεηαλύ ζομμεηεπόκηωκ Εονωπαϊθώκ πωνώκ.

Neuroendocrine Tumor Register Mέλη Σομμεημπή ζημ European NET Registry open to all European nations, πμο απμηειμύκ μέιε ηεξ European Community θαη οπαθμύμοκ ζηε δηαπείνηζε δεδμμέκωκ θαη guidelines πμο πνμζδημνίδμκηαη από ηεκ European Union. Εθμικά Registries Κάζε National Registry πανέπεη data γηα ημ European Registry. Patient documentation γηα ημ European Registry ζα πενηιαμβάκεη ακαδνμμηθά (αζζεκείξ πμο πνωημδηεγκώζηεθακ με ΝΕΤ από 01.01.2000) ΚΑΙ πνμμπηηθά δεδμμέκα.

Neuroendocrine Tumor Register Χώοεπ πξρ ενεδήλωζαμ εμδιαθέοξμ ζρμμεηξςήπ ζηξ European NET Registry database: Με ρπάοςξρζα infrastructure και database: Germany, Spain, Poland, Switzerland, Χωοίπ infrastructure έωπ ζήμεοα: Austria, Czech Republic, France, Italy, Portugal, Slovak Republic, Sweden GREECE

Αζζελείο κε GEP-NET Tκήκα Παζνινγηθήο Φπζηνινγίαο (160) www.neuroendocrine.gr 47

Αζζελείο κε GEP-NET Tκήκα Παζνινγηθήο Φπζηνινγίαο 48

Αζζελείο κε GEP-NET Tκήκα Παζνινγηθήο Φπζηνινγίαο 49

Αζζελείο κε GEP-NET Tκήκα Παζνινγηθήο Φπζηνινγίαο 50

Neuroendocrine Tumor Register

Inverse Probability of Censoring Weighted Analysis (IPCW) in Clinical Trials IPCW: A validated methodology used in several clinical trials Crossover studies: Disease setting Trial Patients, N Agents Patients who selectively crossed over to the superior agent, % Analysis performed Oncology (breast cancer) BIG 1-98 8,010 Letrozole vs Tamoxifen 25 Censoring & IPCW Oncology (neuroendocrine tumours) RADIANT-2 429 Everolimus + Octreotde LAR vs Placebo + Octreotide LAR 58 Censoring & IPCW Oncology (renal cell cancer) RECORD-1 416 Everolimus vs Placebo 27 IPCW AIDS 1 Non-crossover studies: ACTG-021 310 Bactrim vs Pentamidine 7 IPCW Disease setting Trial Patients, N Agents Patients censored, % Analysis performed Atherosclerosis 2 MESA 6,814 Antidepressants 7 IPCW Coronary heart disease 3 MEGA 7,832 Diet vs Pravastatin 72 IPCW Coronary heart disease 4 KLIS 5,640 Conventional treatment vs Pravastatin 3 IPCW Hyperparathyroidism 5 NR 156 Vitamin D 3 45 IPCW 1. Robins JM, et al. Biometrics. 2000;56(3):779-788; 2. Delaney JAC, et al. Pharmacoepidemiol Drug Saf. 2009;18(7):545-553; 3. Yoshida M, et al. Clin Trials. 2007;4(4):318-328; 4. Matsuyama Y, et al. Pharm Stat. 2008;7(3):202-214; 5. Matsuyama Y. Stat Med. 2003;22(5):811-827.

RADIANT-2: Censoring due to New Anticancer Therapy 20 E+O patients censored due to starting new anti-cancer treatment 46 P+O patients censored due to starting new anti-cancer treatment

Rationale for Inverse Probability of Censoring Weights Analysis (IPCW) in RADIANT-2 Imbalance in the loss of events from the local investigator review to the central review 53 events in placebo arm and 23 events in treatment arm were lost High frequency of crossover or new therapy initiation in the placebo + octreotide LAR arm in contrast to everolimus + octreotide LAR More patients with poor prognostic factors were randomized to the everolimus + octreotide LAR treatment arm Statistically significant imbalances in RADIANT-2 in favor of the placebo plus octreotide LAR treatment arm WHO PS 1 45% vs 34%, p<0.05 Lung primary site 15% vs 5%, p<0.05 Prior chemotherapy 35% vs 26%, p<0.05

Summary: Inverse Probability of Censoring Weighted Analysis (IPCW) Rigorous, valid statistical methodology that has been used in large, randomized, phase III trials and observational studies Corrects the bias in informative censoring and adjusts for the imbalances in randomization IPCW methodology allows for a more reliable assessment of the treatment of effect

Probability (%) Probability (%) RADIANT-2: Comparison of IPCWadjusted KM curves for PFS central 100 90 80 E+O IPCW EVE IPCW EVE E+O 100 90 80 P+O IPCW PLB IPCW P+O PLB 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 6 12 18 24 30 36 T ime (months) 0 6 12 18 24 30 36 T ime (months) Placebo+ octreotide LAR affected by the IPCW adjustment more than everolimus + octreotide LAR impact on the IPCW-weighted HR

Scenario 1: Patient on P + O Discrepancies in Investigator/Central Analysis Leading to Informative Censoring 123 / 213 patients received open label everolimus + octreotide LAR March 3 22% tumour growth* Investigator assessment SD SD PD March 10 Patient unblinded Treatment change to E + O Study end Patient is censored Event is lost BL Week 12 Week 24 Week 36 SD Central radiology assessment SD SD March 31 18% tumour growth* P + O = placebo + octreotide LAR E + O = everolimus +octreotide LAR * Disease progression per RECIST 1.0 >20%

Scenario 2: Patient on P + O Discrepancies in Investigator/Central Analysis: No Informative Censoring Investigator assessment March 3 19% tumour growth* Study end SD SD SD BL Week 12 Week 24 Week 36 Patient is not censored Event is captured Central radiology assessment SD SD PD March 31 22% tumour growth* P + O = placebo + octreotide LAR E + O = everolimus + octreotide LAR * Disease progression per RECIST 1.0 >20%

Scenario 3: Patient on E + O Discrepancies in Investigator/Central analysis: No Censoring 69 / 216 patients received subsequent therapies March 3 22% tumour growth* Investigator assessment No new therapy initiated Study end SD SD PD Event may be captured at subsequent radiologic reading No censoring BL Week 12 Week 24 Week 36 SD Central radiology assessment SD SD March 31 18% tumour growth* P + O = placebo + octreotide LAR E + O = everolimus + octreotide LAR * Disease progression per RECIST 1.0 >20%

Summary of IPCW in RADIANT-2 Pre-specified in the protocol Recognized methodology to adjust for different censoring patterns, loss of power and imbalance in baseline characteristics IPCW adjusted PFS HR = 0.60; 95% CI [0.44-0.84]; P = 0.0014 in favor of everolimus + octreotide LAR Pavel M, Hainsworth J, Baudin E, et al. 35 th ESMO Congress 2010; Milan, Italy. Abstract #LBA8