Jaume Capdevila, MD GI and Endocrine Tumor Unit Vall d Hebron University Hospital Developmental Therapeutics Unit Vall d Hebron Institute of Oncology

Jaume Capdevila, MD GI and Endocrine Tumor Unit Vall d Hebron University Hospital Developmental Therapeutics Unit Vall d Hebron Institute of Oncology

OUTLINE Molecular Rationale for the use of SSAs in NETs Antihormonal effect Antiproliferative effect Clinical data of SSAs activity in NETs SSAs in combination with other MTTs

NEUROENDOCRINE NEOPLASMS: WHY SSA? SECRETION PROLIFERATION Hormones Amines (eg, serotonin) Tachykinins Granins (eg, CgA) Growth factors (eg, IGF-1) NEN, Neuroendocrine neoplasms, SSA, somatostatin analogs

CELL BIOLOGICAL MECHANISMS OF ACTION OF SSA hormone secretion auto-/paracrine secretion of growth factors receptor phosphorylation proliferation angiogenesis signal transduction apoptosis cell cycle arrest (G1) Lamberts SW, et al. N Engl J Med. 1996

SOMATOSTATIN RECEPTOR SUBTYPE-BINDING AFINITY OF SSA Grozinsky-Glasberg S, et al. Endocr Relat Cancer 2008

MAJORITY OF PATIENTS ACHIEVE COMPLETE OR PARTIAL CONTROL OF SYMPTOMS ON SSA Symptomatic response 100 (74.2) (71) (77.3) (75) (63.0) (63) (67.5) (63) % of response 75 50 25 Flushing n=53 Diarrhea n=49 25% 57% 74% 89% >50% Improvement Complete response 0 OCT OCT LAR LAN LAN SR+AG Studies n=11 n=7 n=1 n=7 Patients n=261 n=122 n=30 n=185 5-HIAA n=57 68% 5% 0 50 100 Patients with improvement (%) Octreotide Lanreotide

SSA RECEPTORS DOWNSTREAM CASCADE Effect of SSA on phosphorilation of different residues of mtor pathway Grozinsky-Glasberg S, et al. Endocr Relat Cancer 2008

ANTIPROLIFERATIVE EFFECT OF SSA IN PATIENTS WITHOUT DOCUMENTED PD OR ~5% SD 60-70% Toumpanakis C, et al. Semin Oncol 2013

ANTIPROLIFERATIVE EFFECT OF SSA IN PATIENTS WITH DOCUMENTED PD OR ~5% SD 40-45% Toumpanakis C, et al. Semin Oncol 2013

PROSPECTIVE CLINICAL TRIAL IN PROGRESSIVE NETS: SPANISH STUDY (TTD) NET ORIGIN (n=30) n (%) Pancreas 8 (26,7) Gastric 1 (3,3) Duodenum 1 (3,3) Ileum 6 (20,0) Jejunum 3 (10) Caecum 2 (6,7) Right colon 1 (3,3) Lung 4 (13,3) Unknown 4 (13,3) mpfs 12,9 months (IC 95%: 7,9-16,5) Treatment LANREOTIDE AUTOGEL 120 mg every 28 days Martin-Richard M, et al. BMC Cancer 2013

PROSPECTIVE CLINICAL TRIAL IN PROGRESSIVE NETS: SPANISH STUDY (TTD) Partial Response: 4% Stabilization: 89% Progression: 7% Martin-Richard M, et al. BMC Cancer 2013

PROSPECTIVE TRIALS OF SSA IN SMALL INTESTINE NETS 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 Phase III, randomized, double-blind, placebo-controlled 18 centers in Germany (2001 2008) 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 tumor progression or death Rinke A, et al. J Clin Oncol. 2009

PROMID STUDY: GRADE 1 AND LOW LIVER INVOLVEMENT SMALL INTESTINE NETS (81/85 Ki67 <2%) Carcinoid syndr. Hepatic tumor load Per Protocol Analysis Octreotide LAR Placebo N Median PFS, mo Median PFS, mo HR [95% CI] Carcinoid syndrome 33 14.3 5.5 0.23 [0.09-0.57] Inactive tumor 52 28.8 5.9 0.25 [0.10-0.59] Liver involvement 0% 12 13.1 8.2 0.55 [0.10-3.09] Liver involvement 0%-10% 52 29.4 6.1 0.17 [0.08-0.40] Liver involvement 10%-50% 14 11.2 5.5 0.40 [0.10-1.67] Liver involvement >50% 7 4.6 2.8 0.71 [0.11-4.45] Patients, proportion 1.0 0.8 0.6 0.4 0.2 Placebo, 40 events; median, 6.0 months Octreotide LAR, 26 events; median, 14.3 months 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Rinke A, et al. J Clin Oncol. 2009

THE PROMID STUDY: OCTREOTIDE LAR IN MIDGUT NETS WHAT DID WE LEARN? Lessons Octreotide LAR shows antitumor effect in: Midgut tumors Low hepatic tumor burden (<10%) Grade 1 tumors Limitations The efficacy of Octreotide LAR is uncertain in: Non-midgut tumors Higher liver tumor burden (<10%) Grade 2 tumors Non-Progressive disease

THE CLARINET STUDY A randomized double-blind placebo-controlled phase III study of Lanreotide Antiproliferative Response In enteropancreatic NET n = 2 0 4 Patients with GEP-NET Histologically confirmed Measurable (CT / MRI) Grade 1 / grade 2 well / mod differentiated (Ki67 <10%) [WHO 2010 classification] Locally inoperable or metastatic Nonfunctioning only R A N D O M I Z A T I O N ( 1 : 1 ) Lanreotide Autogel 120 mg sc every 28 days Placebo every 28 days Treatment continued until tumor progression or death 12 24 36 48 72 96 we e k s C l i n i c a l T ri a l s. g o v N C T 00353 496 Eu d ra C T 2005-004904 - 35 Primary endpoint: PFS Secondary endpoints: Adverse events, pharmacokinetics, quality of life, CgA serum levels Caplin ME, et al. N Engl J Med. 2014

CLARINET: BASELINE CHARACTERISTICS Lanreotide (n=101) Placebo (n=103) Men, n (%) 53 (52) 54 (52) Age in years, mean (SD) 63.3 (9.8) 62.2 (11.1) NET origin, n (%) Pancreas Midgut Hindgut Unknown/other 42 (42) 33 (33) 11 (11) 15 (15) 49 (48) 40 (39) 3 (3) 11 (11) Tumour progression, n (%) 4 (4) 5 (5) Prior treatment, n (%) 16 (16) 16 (16) Tumour grade, n (%)* 1 (Ki-67: 0 2%) 2 (Ki-67: 3 10%) Unknown Hepatic tumour volume, n (%) 0% >0 10% >10 25% >25 50% >50% 69 (68) 32 (32) 0 16 (16) 33 (33) 13 (13) 23 (23) 16 (16) 72 (70) 29 (28) 2 (2) 18 (17) 40 (39) 17 (17) 12 (12) 16 (16) Chromogranin A, n (%) 1 ULN 1 2 ULN >2 ULN 33 (33) 25 (25) 41 (41) 34 (33) 18 (17) 48 (47) *Ki-67 Unknown thresholds as per World Health Organization (WHO) 2010 classification with values 2 (2) >2 10% assigned to grade 2. 3 (3) Caplin ME, et al. N Engl J Med. 2014

CLARINET: LANREOTIDE PROLONG PFS IN ENTEROPANCREATIC NET Patients Alive and With No Progression, % 100 90 80 70 60 50 40 30 20 10 PFS (intention to treat population) Lanreotide Autogel 120 mg 32 events / 101 patients median, not reached Placebo 60 events / 103 patients median, 18.0 months [95% CI: 12.1, 24.0] 0 0 3 6 9 12 18 24 27 No at risk: Time, months 101 94 84 78 71 61 103 101 87 76 59 43 Lanreotide Autogel vs Placebo P =.0002 HR = 0.47 [95% CI: 0.30, 0.73] 40 0 26 0 62% 22% Caplin ME, et al. N Engl J Med. 2014

CLARINET: LANREOTIDE PROLONG PFS IN ENTEROPANCREATIC NET PFS in midgut vs pancreatic NET Patients Alive and With No Progression, % 100 90 80 70 60 50 40 30 20 10 0 Lan r eot i de A u t ogel 120 m g 8 e v e n t s / 3 3 p a t i e n t s m e d i a n, n o t r e a ch e d Mi d g u t NE T s ( n = 7 3 ) La nr e ot i de Au t o g e l vs p l aceb o P =. 0 0 9 1 HR = 0. 3 5 [ 9 5 % C I : 0. 1 6, 0. 8 0 ] P l a ce b o 2 1 e v e n t s / 4 0 p a t i e n t s m e d i a n, 2 1. 1 m o n t h s [ 9 5 % C I : 1 7. 0, N C ] 0 3 6 9 12 18 24 27 Ti m e, m o nt hs 100 90 80 70 60 50 40 30 20 10 0 Lan r eot i de A u t ogel 120 m g 1 8 e v e n t s / 4 2 p a t i e n t s m e d i a n, n o t r e a ch e d pn E T s (n = 9 1 ) La nr e ot i de Au t o g e l vs p l aceb o P =. 0 6 3 7 HR = 0. 5 8 [ 9 5 % C I : 0. 3 2, 1. 0 4 ] P l a ce b o 3 1 e v e n t s / 4 9 p a t i e n t s m e d i a n, 1 2. 1 m o n t h s [ 9 5 % C I : 9. 4, 1 8. 3 ] 0 3 6 9 12 18 24 27 Ti m e, m o nt hs Caplin ME, et al. N Engl J Med. 2014

CLARINET: LANREOTIDE PROLONG PFS IN ENTEROPANCREATIC NET PFS in grade 1 vs grade 2 (Ki-67<10%) NET Patients Alive and With No Progression, % 100 90 80 70 60 50 40 30 20 10 0 Lan r eot i de A u t ogel 120 m g 1 9 e v e n t s / 6 9 p a t i e n t s m e d i a n, n o t r e a ch e d Grade 1 tumors (n= 141) Grade 2 tumors (n= 61) La nr e ot i de Au t o g e l vs p l aceb o La nr e ot i de Au t o g e l vs p l aceb o P =. 0016 HR = 0. 43 [ 95 % C I : 0. 25, 0. 74 ] 100 P =. 0235 HR = 0. 45 [ 95 % C I : 0. 22, 0. 91 ] Ti m e, m o n t h s 90 80 70 60 50 40 30 Lan r eot i de A u t ogel 120 m g 1 3 e v e n t s / 3 2 p a t i e n t s m e d i a n, n o t r e a ch e d 20 P l a ce b o P l a ce b o 40 e v e n t s / 72 p a t i e n t s 10 19 e v e n t s / 29 p a t i e n t s m e d i a n, 18. 3 m o n t h s [ 95 % C I : 12. 7, 24. 0 ] m e d i a n, 12. 1 m o n t h s [ 95 % C I : 9. 0, 18. 0 ] 0 0 3 6 9 12 18 24 27 0 3 6 9 12 18 24 27 Ti m e, m o n t h s P va l u e d e r i ve d f r o m l o g - r a n k t e st ; H R d e r i v e d f r o m C o x p r o p o r t i o n a l h a z a r d s m o d e l Caplin ME, et al. N Engl J Med. 2014

CLARINET: LANREOTIDE PROLONG PFS IN ENTEROPANCREATIC NET PFS low vs high hepatic tumor load Patients Alive and With No Progression, % 100 90 80 70 60 50 40 30 20 10 0 Lan r eot i de A u t ogel 120 m g 1 4 e v e n t s / 6 2 p a t i e n t s m e d i a n, n o t r e a ch e d Tumor load 25% (n=137) La nr e ot i de Au t o g e l vs p l aceb o P =. 0002 HR= 0. 34 [ 95 % C I : 0. 18, 0. 62 ] 20 P l a ce b o 41 e v e n t s / 75 p a t i e n t s 10 m e d i a n, 21. 1 m o n t h s [ 95 % C I : 17. 6, 24. 4 ] 0 0 3 6 9 12 18 24 27 Ti m e, m o n t h s 100 90 80 70 60 50 40 30 Tu m o r l o a d > 2 5 % ( n = 6 7 ) La nr e ot i de Au t o g e l vs p l aceb o P =. 0 1 7 0 HR= 0. 4 5 [ 9 5 % C I : 0. 2 3, 0. 8 8 ] Lan r eot i de A u t ogel 120 m g 1 8 e v e n t s / 3 9 p a t i e n t s m e d i a n, 2 4. 1 m o n t h s [ 9 5 % C I : 9. 3, N C ] P l a ce b o 1 9 e v e n t s / 2 8 p a t i e n t s m e d i a n, 9. 4 m o n t h s [ 9 5 % C I : 6. 3, 1 2. 0 ] 0 3 6 9 12 18 24 27 Ti m e, m o n t h s P va l u e d e r i ve d f r o m l o g - r a n k t e st ; H R d e r i v e d f r o m C o x p r o p o r t i o n a l h a z a r d s m o d e l ; N C, n o t ca l cu l a b l e Caplin ME, et al. N Engl J Med. 2014

CLARINET: LANREOTIDE IS WELL TOLERATED AND EFFECTIVE WITHOUT COMPROMISING QUALITY OF LIFE Adverse events (safety population) Lanreotide shows a good safety profile consistent with other SSA studies Diarrhea most prominent adverse events Quality of life is unchanged (EORTC-QLQ C30) Caplin ME, et al. N Engl J Med. 2014

CLARINET OPEN LABEL EXTENSION STUDY PFS (40 patients with stable disease [SD] continuing on lanreotide: LAN-LAN group) Patients Alive and With No Progression, % 100 90 80 70 60 50 40 30 20 10 0 Core study Central radiological assessment Placebo 61 events/103 patients median, 18.0 months [95% CI: 12.1, 24.0] Extension study Local radiological assessment Lanreotide Autogel 45 events/101 patients (core: 32 events/101 patients; OLE: 13 events/40 patients) median, 32.8 months [95% CI: 30.9, 68.0] 40 patients with SD while receiving lanreotide in the core study continued into the Open Label Extension study 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time From Randomization in Core Study, months 101 84 71 61 51 36 25 17 11 7 5 5 1 0 103 87 59 43 26 0 Caplin M, et al. J Clin Oncol. 2014;32(5s): Abstract 4107

CLARINET STUDY: LANREOTIDE IS EFFECTIVE IN PROGRESSIVE ENTEROPANCREATIC NET Time to progression (TTP) in placebo patients with progressive disease (PD) (32 patients with PD starting on lanreotide: PBO-LAN group) Patients Alive and With No Progression, % 100 90 80 70 60 50 40 30 20 10 0 Switched to lanreotide Autogel 17 events/32 patients median, 14.0 months [95% CI: 10.1, NC] 0 6 12 18 24 30 36 42 48 54 Time From Centrally Assessed PD in Core Study, months Caplin M, et al. J Clin Oncol. 2014;32(5s): Abstract 4107

CONCLUSIONS CLARINET Lanreotide substantially prolongs PFS in metastatic well / moderately differentiated enteropancreatic NETs Median PFS with lanreotide not reached vs 18 months with placebo (P =.0002) 53% risk reduction for progression / death Antiproliferative effect was observed In patients with grade 1 and grade 2 tumors (Ki67 <10%) In patients with low and high hepatic tumor load In patients with primary tumors in small intestine and pancreas In patients with progressive disease (Open Label Extension Study) Very good tolerability consistent with previous studies Data supports important role in treatment algorithm for GEP-NETs Caplin ME, et al. N Engl J Med. 2014 Caplin M, et al. J Clin Oncol. 2014;32(5s): Abstract 4107

BLOCKING DIFFERENT PATHWAYS IN NETS VEGFR 1 3, PDGFR, KIT, RET SSR 1 5 Ca ++ K + SSA C-SRC Sunitinib Phospholipase C RAS PI3K Adenylate Cyclase STAT JAK-2 BRAF AKT PTEN MAPK mtor Everolimus Hormonal secretion Angiogenesis Proliferation Immune response Capdevila J, et al. Ann Oncol 2011

EVIDENCE OF SSA-MMT COMBINATIONS 27% concomitant SSAs 40% concomitant SSAs Raymond E, et al. N Engl J Med 2011; Yao JC, et al. N Engl J Med 2011; Pavel et al, Lancet 2011

MECHANISM OF RESISTANCE TO MTOR INHIBITION IGFR-1 Feedback activation of AKT following mtor inhibition by rapalogs IRS PI3K AKT PTEN PDK1 pakt-s473 staining PIP3 Tumor sample of a patient on treatment with everolimus pre-therapy on-therapy Tuberin Rheb TORC1 S6K S6 4EBP1 Modified from Di Cosimo S, et al. ASCO 2010 Tabernero J et al., J Clin Oncol 2008

MECHANISM OF RESISTANCE TO MTOR INHIBITION IGFR-1 Feedback activation of AKT following mtor inhibition by rapalogs IRS PI3K PTEN PDK1 AKT pakt-s473 staining PIP3 Tumor sample of a patient on treatment with everolimus pre-therapy on-therapy Tuberin Rheb TORC1 S6K S6 4EBP1 Modified from Di Cosimo S, et al. ASCO 2010 Tabernero J et al., J Clin Oncol 2008

MECHANISM OF RESISTANCE TO MTOR INHIBITION IGFR-1 IRS Feedback activation of AKT following mtor inhibition by rapalog PI3K AKT PTEN PDK1 pakt-s473 staining PIP3 Tumor sample of a patient on treatment with everolimus pre-therapy on-therapy Tuberin Co-treatment with IGFR1 inhibitor prevents feedback activation of AKT by mtor inhibition in preclinical models Rheb TORC1 S6K S6 4EBP1 Modified from Di Cosimo S, et al. ASCO 2010 Tabernero J et al., J Clin Oncol 2008 Di Cosimo S, et al. J Clin Oncol 2007

RETROSPECTIVE STUDY OF LANREOTIDE PLUS MTT IN SPANISH PATIENTS WITH NET Study identified 133 patients with NET from 35 Spanish medical oncology departments N=64 (48%) had pancreatic NET Characteristics Patients (N=133) Male/Female, n (%) 70 (52.6)/63 (47.4) Median age, years (range) 59.4 (16 83) ECOG PS, n (%) 0/1 45 (33.8)/65 (48.9) 2/3 22 (16.5)/1 (0.8) Location of primary tumour Foregut 85 (64.0) Midgut 30 (22.6) Hindgut 6 (4.6) Unknown 14 (10.5) Tumour functionality, n (%) Nonfunctioning/Functioning 92 (69.2)/41 (30.8) Capdevila J, et al. ESMO 2012

PROGRESSION-FREE SURVIVAL Capdevila J, et al. ESMO 2012

SEVERAL CLINICAL TRIALS IN NETS EXPLORING SSA IN COMBINATION WITH MMT Randomized Phase III study (SWOG0518) Octreotide + IFN vs Octreotide + Bevacizumab Randomized Phase II study (SUNLAND) Lanreotide +/- Sunitinib Randomized Phase II study (COOPERATE-II) Everolimus +/- Pasireotide Randomized Phase II study (GETNE1107) Octreotide +/- Axitinib www.clinicaltrials.gov

SEVERAL CLINICAL TRIALS IN NETS EXPLORING SSA IN COMBINATION WITH MMT Non-Randomized Phase II study (NCT01782443) Aflibercept + Octreotide Non-Randomized Phase II study (NCT01121939) Bevacizumab + Pertuzumab + Octreotide Non-Randomized Phase I study (NCT01204476) Cixutumumab + Everolimus + Octreotide Non-Randomized Phase II study (NCT02231762) Lanreotide + Temozolomide www.clinicaltrials.gov

TAKE-HOME MESSAGES SSA have become the cornerstone of the treatment of symptomatic advanced NETs There is a strong molecular rationale for an action of SSA as antiproliferative agents The CLARINET study has clearly demonstrated efficacy in tumor growth control of enteropancreatic NETs Combination of SSA with other MTT is of medical interest; Need to be confirmed by ongoing studies.

Muchas gracias por vuestra atención jacapdevila@vhebron.net jcapdevila@onco.cat