Medical treatment non-pancreatic NETs

Medical treatment non-pancreatic NETs Prof Juan Valle Professor and Honorary Consultant Institute of Cancer Sciences University of Manchester The Christie ENETS Centre of Excellence ESMO Preceptorship on GI neuroendocrine tumours (NETs) Leuven, Belgium, 28-29 November 2014

DISCLOSURES Honoraria: Novartis, Ipsen, Pfizer, Keocyt, SIRTex, Celgene Grant Funding: Novartis, AstraZeneca

OVERVIEW Therapies for advanced disease Interferon Somatostatin analogues Chemotherapy Targeted therapies PRRT Liver-directed therapies HAE TACE RE surgery etc.

Interferon Mechanism of action Binding to type-i IFN receptors 1 Activation of JAK-STAT pathways 1 Stimulation of T-cells 2 Inducing cell-cycle arrest (in G1 and G0) 2 Inhibit angiogenesis 2 Induce up-regulation of somatostatin receptors 3 1 Platanias Nat Rev Immunol. 2005 May;5(5):375-86 2 Detjen et al Gastroenterology 2000 Apr;118(4):735-48 3 Hofland et al J Clin Endocrinol Metab. 1999 Sep;84(9):3336-43

Interferon in NETs Results Symptomatic improvement 30-70% Biochemical response 50-60% Introduced in 1982 1 By 2012 2 37 studies 679 patients Doses 3-5MU sc x3/week Toxicities flu-like syndrome Fatigue Myelosuppression Auto-immune disorders Depression Radiological response rate 10% Stable disease 70% Limitations Case series Retrospective Heterogeneous Trial methodology 1 Öberg et al. New Engl J Med 1982;309:129 2 Öberg Best Pract Res Clin Gastroenterology 2012;26:833 841

Interferon in NETS phase III studies Study Eligibility n Comment Kölby 1 Midgut, post surgery and HAE 35 Octreotide 100µg bd 200µg tds 230 patients planned initially 5YS: 57% vs. 37% (NS) 33 Octreotide 100µg bd 200µg tds + IFN 3-5MU x3/wk Improved PFS: HR 0.28 [95%CI 0.16-0.45, p=0.008] 1 Kölby et al Br J Surg. 2003 Jun;90(6):687-93 2 Faiss et al J Clin Oncol. 2003 Jul 15;21(14):2689-96. 3 Arnold et al Clin Gastroenterol Hepatol. 2005 Aug;3(8):761-71

Interferon in NETS phase III studies Study Eligibility n Comment Kölby 1 Faiss 2 Midgut, post surgery and HAE Progressive (within 3-months), welldifferentiated GEP 35 Octreotide 100µg bid 200µg tid 230 patients planned initially 5YS: 57% vs. 37% (NS) 33 Octreotide 100µg bid 200µg tid + IFN 3-5MU x3/wk Improved PFS: HR 0.28 [95%CI 0.16-0.45, p=0.008] 25 Lanreotide 1mg tid No difference in 1-yr progression rate: 56% in all three arms 27 IFN 5MU x3/wk 28 Lanreotide 1mg tid + IFN 5MU x3/wk No difference in RR Combination arm associated with greater reduction of symptoms (p=0.037) 1 Kölby et al Br J Surg. 2003 Jun;90(6):687-93 2 Faiss et al J Clin Oncol. 2003 Jul 15;21(14):2689-96. 3 Arnold et al Clin Gastroenterol Hepatol. 2005 Aug;3(8):761-71

Interferon in NETS phase III studies Study Eligibility n Comment Kölby 1 Faiss 2 Arnold 3 Midgut, post surgery and HAE Progressive (within 3-months), welldifferentiated GEP Progressive, welldifferentiated, GEP 35 Octreotide 100µg bid 200µg tid 230 patients planned initially 5YS: 57% vs. 37% (NS) 33 Octreotide 100µg bid 200µg tid + IFN 3-5MU x3/wk Improved PFS: HR 0.28 [95%CI 0.16-0.45, p=0.008] 25 Lanreotide 1mg tid No difference in 1-yr progression rate: 56% in all three arms 27 IFN 5MU x3/wk 28 Lanreotide 1mg tid + IFN 5MU x3/wk No difference in RR Combination arm associated with greater reduction of symptoms (p=0.037) 51 Octreotide 200µg tid 250 patients planned initially OS in combination arm 51 54 Octreotide 200µg tid + IFN 4.5MU x3/wk vs. 35 mo HR 0.82 [95%CI 0.52 1.29, NS] 1 Kölby et al Br J Surg. 2003 Jun;90(6):687-93 2 Faiss et al J Clin Oncol. 2003 Jul 15;21(14):2689-96. 3 Arnold et al Clin Gastroenterol Hepatol. 2005 Aug;3(8):761-71

CASTOR DOTATATE 177Lu-DOTA octreotate vs. interferon in non-pancreatic gastrointestinal NETs Study Status: Ongoing (not recruiting) Estimated Primary Completion: Oct, 2016 Design: Randomised, parallel, open study assessing the benefit of Peptide Receptor Radionuclide Therapy (PRRT) versus interferon α-2b Patients with non- pancreatic gastrointestinal NETs, somatostatin analogue-resistant disease, ECOG status 1 N=60 Phase 3 RANDOMISATION 177Lu-octreotate infusions in fixed activities of 7,4 GBq each, given 8-11 weeks apart, IV with an amino acid infusion Interferon α-2b 5MU Units SC every second day Primary endpoint: PFS (RECIST) Sponsor: Jules Bordet Institute 177Lu-octreotate is co-infused over 15-30 minutes 30 minutes after the beginning of the amino acid solution Secondary endpoints: Treatment response, AEs Key Exclusion Criteria: Resectable disease with curative intent at enrolment Prior treatment with interferon Key Implications: This phase 3 study focuses on patients who have progressed on a somatostatin analogue (non-pancreatic NETS), patients were selected by positive uptake on 68 Ga octreotate PET-CT 1. Randomised Phase III of PRRT Versus Interferon (CASTOR). Available at: http://www.clinicaltrial.gov/ct2/show/nct01860742 CASTOR: Carcinoid Tumours After Failure of Somatostatin Analogues

SOMATOSTATIN ANALOGUES The median survival of patients diagnosed with NETs and distant metastases was significantly longer in 1988-2004 compared to 1973-1987 timeframe (SEER database) * Data from an analysis of 35,825 cases of NETS identified in the SEER registries Yao JC et al. J Clin Oncol 2008;26:3063 3072

G protein SHP1 sst 2 NF-KB JNK PI3K GSK3β p53 Zac1 Apoptosis PDK1 Akt Molecular pathway of SSAs mtor p70s6k direct anti-proliferative effect PTPŋ SHP2 Src MAPK sst 2 Cell growth G protein SHP1 p27 PKG sst 5 G protein cgmp sst 2 and sst 5 binding both down-regulate MAPK sst 2 binding mediates P13K/Akt/mTOR pathway and SHP1 signaling Antiproliferative effect also mediated via protein tyrosine phosphatase (PTPase) modulation Theodoropoulou M et al. Cancer Res 2006;66:1576 1582 Florio T et al. Front Biosci 2008;13:822 840 Grozinsky-Glasberg S et al. Neuroendocrinology 2008;87:168 181

Proposed mechanism of anti-proliferative effect Anti-proliferative effect of octreotide Binding of the somatostatin receptor on tumour cells Systemic effect Direct anti-proliferative effect Indirect anti-proliferative effect Inhibition of cell cycle Inhibition of growth factor effects Proapoptotic effect Inhibition of growth factor and trophic hormones Inhibition of angiogenesis Immune system modulation Susini C & Buscail L. Ann Oncol 2006;17:1733 1742

Early prospective studies suggesting anti-tumour activity of octreotide Anti-tumour activity of octreotide in patients with progressive GEP-NETs Reference Regimen Response Saltz et al Octreotide sc 3 x 200 μg/d (n=34) SD in 50% of patients for 2 27 months 1993 1 Arnold et al Octreotide sc 3 x 200 μg/d (n=52) SD in 37% of patients for 3 60 months 1996 2 Di Bartolomeo et al. 1996 3 Arnold et al 2005 4 Panzuto et al 2006 5 Octreotide sc: 3 x 500 μg/d (n=23) Octreotide sc: 3 x 1000 μg/d (n=35) Octreotide sc 200 μg tid (n=51) OR Octreotide sc 200 μg tid + Interferon-α 4.5 x 106 IU tiw (n=54) Octreotide LAR 30 mg/28d (n=20) Lanreotide SR 60 mg/28d (n=11) SD in 47% of patients for 6 32 months PR in 3% of patients No significant difference between treatment arms SD or PR in 45% at 3 months; 28% at 6 months; 18% at 12 months (PR=2%) SD in 45.2% of patients for 3 6 months 1. Saltz L et al. Cancer 1993;72:244 248 2. Arnold R et al. Gut 1996;38:430 438 3. Di Bartolomeo M et al. Cancer 1996;77:402 408 4. Arnold R et al. Clin Gastroenterol Hepatol 2005;3:761 771 5. Panzuto F et al. Ann Oncol 2006;17:461 466 SD=stable disease PR=partial response The tiw=three Christie times/week NHS Foundation Trust

Summary of non-randomized clinical trials In recent years, accumulating laboratory and clinical data has supported SSAs role as antiproliferative agents. Further research efforts are underway. CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease Adapted from Strosberg J, et al. World J Gastroenterol. 2010;16:2963 70

Limitations of small studies Many patients have indolent disease ( stable disease ) anyway disease progression not mandated at study entry for all studies Studies included heterogeneous tumour populations NETs were of different organ sites and biological behaviour Heterogeneity with respect to prior therapies, very few treatment-naïve patients Studies were not designed or powered to evaluate tumour control Lack of placebo-control

PROMID: evaluation of the antitumour activity of octreotide LAR Phase III randomised, double-blind, placebo-controlled study Patients with mid-gut NETs treatment-naïve histologically confirmed locally inoperable or metastatic well differentiated measurable (CT/MRI) functioning or nonfunctioning RANDOMISATION (1:1) Octreotide LAR 30mg i.m. every 28 days Placebo i.m. every 28 days Treatment continued until tumour progression or death Months 3 6 9 12 15 18 Primary endpoint: Time to progression (blinded central review) Secondary endpoints: objective response rate, OS, quality of life, safety Rinke et al. J Clin Oncol 2009;27:4656-4663.

PROMID: Patient demographics Octreotide LAR (n=42) Placebo (n=43) Total (n=85) Median age, years (range) 63.5 (38 79) 61.0 (39 82) 62.0 (38 82) Sex male (%) female (%) 47.6 52.4 53.5 46.5 50.6 49.4 Time since diagnosis, months (range) 7.5 (0.8 271.2) 3.3 (0.8 109.4) 4.3 (0.8 271.2) Karnofsky score 80 >80 16.7% 83.3% 11.6% 88.4% 14.1% 85.9% Carcinoid syndrome* 40.5% 37.2% 38.8% ~60% Nonfunctioning Resection of primary 69.1% 62.8% 65.9% Hepatic tumour load 0% 0 10% 10 25% 25 50% 50% 16.7% 59.5% 7.1% 11.9% 4.8% 11.6% 62.8% 4.7% 9.3% 11.6% 14.1% 61.2% 5.9% 10.6% 8.2% ~75% <10% liver involved Octreoscan positive 76.2% 72.1% 74.1% Ki-67 up to 2% 97.6% 93.0% 95.3% ~95% G1 CgA elevated 61.9% 69.8% 65.9% Rinke et al. J Clin Oncol 2009;27:4656-4663. * not requiring octreotide for symptom control

PROMID: Pre-planned interim analysis Progression-free survival Event-driven analysis following 64 events Actual events at time of interim analysis: 67 tumour progressions and 16 deaths 85 patients from the planned 162 were enrolled at the time of the interim analysis Octreotide LAR 30 mg resulted in a median TTP of 14.3 months compared to 6.0 months with placebo, p=0.000072 Rinke et al. J Clin Oncol 2009;27:4656-4663.

PROMID: Exploratory sub-groups Greatest benefit was seen in patients with Hepatic tumour load 10% (P<0.0009) Resected primary (P<0.0104) KP >80 Octreotide LAR 30mg provided improved TTP Functioning or non-functioning NETs Elevated or non-elevated CgA Any age Arnold R. Presented at ASCO-GI 2009

Limitations of PROMID Balance of study arms Longer time since diagnosis in LAR vs. placebo (7.5 vs. 3.3 mo, p=0.0096) In practice, most patients do not have <10% liver involvement Not effective? vs. sub-optimal dose? Vast majority (97.6%) of patients had Ki-67: 2% What about intermediate grade (Ki67: 2-20%) 76% of patients had positive octreotide scan correlation not described No disease progression mandated at study entry: What does stable disease mean?

Controlled study of Lanreotide Anti-proliferative Response In NET (CLARINET) N=204 Patients with mid-gut and pancreatic NETs histologically confirmed locally inoperable or metastatic measurable (CT/MRI) well / mod differentiated non-functioning only Prior therapy allowed RANDOMISATION (1:1) Lanreotide Autogel 120 mg s.c. every 28 days Placebo s.c. every 28 days Treatment continued until tumour progression or death Primary end-point: Progression-free survival Secondary endpoints: AE, PK, QoL, CgA ClinicalTrials.gov identifier: NCT00353496 Caplin et al N Engl J Med 2014;371:224-33.

CLARINET study population baseline characteristics Most tumours originated in the pancreas or small intestine Most tumours were stable in size at study entry and most patients have had no previous tumour therapy

CLARINET study primary endpoint

CLARINET study primary endpoint

Differences in study design PROMID CLARINET COOPERATE-2 Somatostatin analogue Octreotide Lanreotide Pasireotide Population Midgut All GEP pnet Progression at baseline No No Yes Prior therapy received 0% 15%? Grade 1 95% 69%? Grade 2 5% 30% (Ki67: 2-10%)?

Design: SIG-NET Pasireotide LAR vs. Octreotide LAR metastatic carcinoid tumour Multicentre, randomised, double-blind, parallel group study comparing the efficacy of pasireotide LAR and octreotide LAR in metastatic carcinoid tumour Patients with carcinoid tumours and symptoms (diarrhoea and/or flushing) that are not adequately controlled by somatostatin analogues (SSTa) N=110 RANDOMISATION 1:1 Pasireotide LAR 60 mg IM once every 28 days for 6 months with dose decreased to 40 mg for tolerability (n= 53) Primary endpoint: Symptom response Phase 3 Octreotide LAR 40 mg IM once every 28 days for 6 months with dose decreased to 30 mg for tolerability (n=57) Sponsor: Novartis In addition to LAR treatment, pasireotide SC bid or octreotide SC tid rescue as needed to end of study in 2 treatment groups respectively Secondary endpoints: Symptom response, TRR, DCR, QoL, DoR Key Exclusion Criteria: Patients receiving radiolabeled SSTa within 3 months or cytotoxic chemotherapy or interferon therapy within 4 weeks Patients on anti-diabetics, poorly controlled blood glucose, malabsorption syndrome, cholelithiasis, or diarrhoea Key Implications: Comparison of symptom control in patients with carcinoid syndrome between octreotide LAR (standard arm) and pasireotide (somatostatin analogue with higher affinity for 4 of the 5 somatostatin receptors [especially sst5] compared with octreotide) Although the symptom control was very similar between the two drugs, there appears to be a longer progressionfree survival with pasireotide This needs to be validated in a prospective study (particularly in light of the CLARINET and PROMID studies 1. Efficacy and safety of pasireotide long acting release vs. octreotide long acting release in patients with metastatic carcinoid disease. Available at: http://www.clinicaltrials.gov/show/nct00690430 2. SIG-NET clinical study summary. Available at: http://www.montefiore.org/body.cfm?id=2342&action=detail&ref=48 3. Wolin E.M., et al. Poster presented at North American NeuroEndocrine Tumour Symposium, Charleston, South Carolina, USA, October 04 05, 2013 SIG-NET: SOM230 InvestiGated in NeuroEndocrine Tumour

SIG-NET Pasireotide LAR vs. Octreotide LAR metastatic carcinoid tumour Wolin et al J Clin Oncol 29: 2011 (suppl; abstr 4075) ASCO 2013 Manuscript submitted

Öberg et al Annals of Oncology 23 (Supplement 7): vii124 vii130, 2012 CHEMOTHERAPY

Response rates Tools of the trade chemotherapy in practice Highest with poorly differentiated and anaplastic tumours (70%, cisplatin and etoposide), responses short-lasting Pancreatic NETs: 40-70% with STZ, dacarbazine, 5FU and doxorubicin-based regimens Low RR with midgut carcinoids: 15-30%, lasting 6-8 months (same agents) Patients should be entered into trials, where possible

Chemotherapy for non-pancreatic tumours? Streptozocin-5FUcisplatin (FCiSt) regimen N=82 patients (pancreas [49], GI [9], lung [8], ovary [1], UKP [15]) Histological grade predicts response Response rate: low grade 14% intermediate grade 34% high grade 60% (p=0.025) So does mitotic index score (p=0.008) and Ki67 Turner NC et al. Br J Cancer. 2010 Mar 30;102(7):1106-12. Öberg et al Annals of Oncology 23 (Supplement 7): vii124 vii130, 2012 Not primary site of tumour!

TARGETED THERAPIES

RADIANT-2 Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome Core phase (double-blind phase) Patients with advanced (unresectable or metastatic), low/intermediate grade NET; WHO performance status 2 N=429 Phase 3 RANDOMISATION 1 Everolimus 10 mg daily orally plus octreotide 30 mg IM every 28 days Placebo 10 mg daily orally plus octreotide 30 mg IM every 28 days Primary endpoint: PFS (RECIST) Sponsor: Novartis Following core phase, patients to enter in an openlabel extension phase, receiving open-label everolimus Patients with carcinoid syndrome (regardless of the site of primary tumour Progressive disease (within 12 months) G1 and G2 tumours Pavel et al Lancet 2011; 378: 2005 12

RADIANT-2 Patient Demographics Pavel et al Lancet 2011; 378: 2005 12

RADIANT-2 Primary Endpoint results Central Review Primary endpoint PFS Adjusted for two interim analyses, the pre-specified boundary at final analysis was p 0 0246. Local Review Pavel et al Lancet 2011; 378: 2005 12

RADIANT-2 Exploratory subgroup analysis

Early signal of clinical activity of VEGF inhibition in NETs Sunitinib 1 (4/2 weekly) Phase I n=28 1 pt with rectal NET; PR Phase II PNET n=66 11pts PR (17%) PFS 10mth NET n=40 1pt PR PFS 8mth PNET (everolimus alone) n=115 11pt PR (10%) PFS 10mth PNET (everolimus with SSA) n=45 2pt PR (4%) PFS 17mth 1 Faivre S, JCO 2006

Early signal of clinical activity of VEGF inhibition in NETs Randomised phase II study Metastatic carcinoid tumour (GI and lung, not pnet) 1 line of chemo Stable on Octreotide LAR n=44 Bevacizumab 15 mg/kg q3w 18 weeks Peg-IFN 0.5ug/kg qw Bevacizumab + Peg-IFN Until PD Primary endpoint: Response Rate Endpoint % RR (Bev alone) 18% + 77% SD RR (Peg-IFN) 0% + 68% SD Hypertension more common with BEV (18% vs. 0%) Neutropenia more common with Peg-IFN (14% vs. 0%) No differences in fatigue, nausea, vomiting, headache. Yao J C et al. JCO 2008;26:1316-1323

Early signal of clinical activity of VEGF inhibition in NETs BEV associated with sig. decrease in tumour blood flow (functional CT): 49% at Day 2, 28% at week 18 (p<0.01) No change with Peg-IFN Phase III study ongoing [SWOG S0518, NCT00569127] Yao J C et al. JCO 2008;26:1316-1323

Design: SWOG-S0518 Octreotide acetate (Sandostatin) Octreotide and IFN-α vs. octreotide and bevacizumab in carcinoid tumour Study Status: Ongoing (not recruiting) Estimated Primary Completion: Jan, 2015 Multicentre, randomised, open-label study comparing octreotide depot and IFN-α vs. octreotide depot and bevacizumab in poor prognosis carcinoid patients Phase 2 study results showed PFS to be superior in bevacizumab group than interferon group at week 18 Patients with metastatic/locally advanced, high-risk NET, Low/intermediate grade NET, Zubrod performance status 0-2 N=400 Phase 3 RANDOMISATION IFN α-2b, 0.5μg/kg, SC, on days 1, 3, 5, 8, 10, 12, 15, 17 and 19, plus octreotide, IM Bevacizumab, 15mg/kg, IV over 30-90 mins, plus octreotide, IM Primary endpoint: PFS (central review) Sponsor: NCI, SWOG Treatment repeated every 21 days in the absence of disease progression or unacceptable toxicity Secondary endpoints: OS, TTF, OR, AEs Key Exclusion Criteria: Prior interferon, bevacizumab, or any other therapy targeting VEGF or VEGF receptors Concurrent interferon to control carcinoid syndrome Key Implications: All patients in this large phase 3 study receive octreotide and either interferon (based on multiple historical studies) or bevacizumab (based on the BETTER study) 1. Octreotide acetate and recombinant interferon alfa-2b or bevacizumab in treating patients with metastatic or locally advanced, high-risk neuroendocrine tumour. Available at: http://www.clinicaltrials.gov/show/nct00569127 2. Protocol Abstract: S0518. Available at: http://www.swog.org/visitors/viewprotocoldetails.asp?protocolid=2076 3. Bevacizumab (Avastin) with octreotide (Sandostatin) for high-risk carcinoid tumours first or second line. Dec 2011. NHSC 4. Kulke M H., et al. Poster presented at: American Society of Clinical Oncology (ASCO); June 3-7, 2011; Chicago; IL, USA

Specific/selective tyrosine kinase inhibitors (TKIs) in oncology Name Selective Target Cancer (Examples) Afatinib HER2, EGFR NSCLC, squamous cell carcinoma of the head and neck, breast cancer Canertinib EGFR, HER2, 4 Head and neck, breast, and NSCLC, ovarian cancer Cediranib VEGFRs NSCLC, kidney and colorectal cancer CP-673451 PDGFRs NSCLC, colon carcinomas, glioblastoma Crizotinib MET NSCLC, anaplastic large cell lymphoma, neuroblastoma Dacomitinib EGFR NSCLC, gastric, head and neck cancer, glioma Erlotinib EGFR NSCLC, pancreatic cancer EMD1214063 MET NSCLC EMD1204831 MET NSCLC Gefitinib EGFR NSCLC, AML Icotinib EGFR NSCLC Lapatinib HER-2, EGFR Breast cancer Lenvatinib VEGFR2, 3 Approved for thyroid cancer in Japan LY2801653 Met, RON NSCLC Neratinib EGFR, HER2 NSCLC, breast cancer PD-173074 FGFRs NSCLC, gastric carcinoma, breast cancer Tandutinib FLT3 RCC, CML Tivantinib MET RCC, breast cancer Tivozanib VEGFR1, 2, 3 RCC, breast cancer Vatalanib VEGFR2 NSCLC, DLBCL, colorectal adenocarcinoma Adapted from Hojjat-Farsangi M. Int J Mol Sci. 2014 Aug 8;15(8):13768-801

Multi-targeted tyrosine kinase inhibitors (TKIs) in oncology Name Target Molecules (Examples) Cancer (Examples) Amuvatinib ALK, MER, KIT, RET, PDGFRs, FLT3, RAD 51 NSCLC Axitinib VEGFRs, PDGFRs, KIT RCC Cabozantinib (XL184) VEGF, RET, MET, NTRKB, TIE2, AXL Medullary thyroid cancer Dasatinib BCR-ABL, SRC, KIT, PDGFRs, EPH, CSK CML, ALL Foretinib VEGFR2, MET NSCLC, breast, gastric, papillary renal cancer Golvatinib VEGFR2, MET Gastric cancer, HCC, glioblastoma, melanoma Imatinib ABL, KIT, PDGFRs GIST, leukemias MGCD-265 MET, VEGFRs, TIE2, RON NSCLC Nilotinib BCR-ABL, KIT, LCK, EPHA3, 8, DDR1, 2 CML Pazopanib PDGFRs, VEGFRs Advanced RCC, advanced soft tissue sarcoma Ponatinib BCR-ABL, PDGFRα, SRC, KIT, FGFR, VEGFRs CML, philadelphia chromosome positive ALL Regorafenib TIE2, PDGFRs, RET, KIT, B-RAF Metastatic colon cancer Sorafenib VEGFRs, PDGFRs, B-RAF, MEK, ERK Advanced RCC, hepatocellular carcinoma Sunitinib VEGFR2, PDGFRβ, KIT, RET, CSF1R, FLT3 RCC, GIST, pnet Vandetanib EGFR, VEGFRs, RET, Tie-2, FGFR1 Metastatic medullary thyroid cancer Adapted from Hojjat-Farsangi M. Int J Mol Sci. 2014 Aug 8;15(8):13768-801

SUNLAND sunitinib versus placebo in combination with lanreotide in patients with progressive advanced/metastatic midgut carcinoid tumours Randomised phase II, double-blind, placebo-controlled study Patients with mid-gut NETs well differentiated (G1, G2) functioning (CgA and 5HIAA >1.5xULN) progression within 12 months measurable (CT/MRI) N=104 RANDOMISATION (1:1) Lanreotide 120 mg / 28d + Sunitinib 37.5 mg CDD Lanreotide 120 mg / 28d + placebo Treatment continued until tumour progression or death Primary endpoint: PFS Secondary endpoints: OS, RR, DoR, quality of life, safety Recruiting 2012 2015 (CI: Pr Eric Raymond) ClinicalTrials.gov identifier: NCT01731925

Sunitinib Following Hepatic Artery Embolisation in Metastatic NET Results Sunitinib days 1 28 in a 42-day cycle, starting 7 days after each HAE and ending 7 days before subsequent HAE (6-weekly) Amongst 39 treated patients: PR: 28 patients (72%) SD: 8 patients (20%) PD: 3 patients (8%) Median PFS, 18 months 2-year OS, 78% % Change in Tumor Measurements 100 80 60 40 20 0-20 -40 1 6 11 16 21 26 31 36 Serum VEGF levels increased by an average of 34% (51 pg/ml) -60-80 Sunitinib 37.5 mg/day by CDD could be administered safely following HAE -100 Strosberg J, et al. Annals of Oncology 2013;23:2335 2341

Other ongoing studies with sunitinib A Randomized Phase II Double-Blind Trial of Sunitinib vs. placebo in combination with Lanreotide in Patients with Progressive Advanced / Metastatic Midgut Carcinoid Tumours - NCT01731925 Antitumor Efficacy of Peptide Receptor Radionuclide Therapy With 177 Lutetium -Octreotate Randomized vs. Sunitinib in Unresectable Progressive Well-differentiated Neuroendocrine Pancreatic Carcinoma: First Randomized Phase II - NCT02230176

Pathways to New Agents Pavel, M. Neuroendocrinology 2013;97:99 112

At a glance Intestinal pnet 6mo-PFS ORR 6mo-PFS ORR Sunitinib (phase III) - - 71% 9% Sunitinib (phase II) 73% 2% 70% 11% Pazopanib 68% 0% 81% 19% Sorafenib 40% 10% 61% 10% Axitinib???? Cabozantinib????

Who benefits most? Biomarkers Unanswered questions (i) Molecular diagnosis

Unanswered questions (ii) How do we deal with emerging resistance? Sequencing of therapies Optimal combination Role earlier in the disease? Applicability to other entities Different grade Different site of origin

SUMMARY Treatment options less developed for intestinal NETs vs. pancreatic NETs Somatostatin analogues have an established role: control of hormonal secretion Anti-proliferative effect Interferon may be considered for selected patients symptoms uncontrolled with SSAs The role of chemotherapy is less clear, but may be considered for selected patients Targeted therapies show promise: RADIANT-2 study suggests benefit (not licensed or reimbursed) Multiple TKIs under investigation IMPROVED RESEARCH METHODOLOGY AND HIGHER PROFILE OF NETS MEAN EXCITING YEARS AHEAD

Thank you

BACK-UP SLIDES

Sorafenib inhibits several tyrosine protein kinase receptors (VEGFR and PDGFR) and Raf Kinases (CRaf) A phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study ECOG PS 0-2 1 prior chemotherapy Prior interferon and prior/concurrent octreotide at a stable dose allowed. sorafenib 400 mg po BID Primary endpoint: response RECIST Two cohorts (i.e. Carcinoid and pnet) (separate 2-stage phase II designs). Results: N= 93 pts (50 Carcinoid, 43 pnet) Response Rates: Carcinoid: 4/41 (10%); pnet: 4/41 (10%) 6-month PFS: Carcinoid: 8/20 (40%); pnet: 14/23 (61%) Toxicity: Grade 3 4 toxicity occurred in 43% o skin (20%); GI (7%); fatigue (9%) Conclusions: Sorafenib at 400 mg po BID has modest activity in metastatic neuroendocrine tumors, with frequent grade 3-4 toxicity. T. J. Hobday et al, ASCO JCO 2007;25:18S (abstr 4504)

SORNET: Efficacy study of Sorafenib and cyclophosphamide to treat NETs 1 NCT00605566 N=22 patients Sorafenib: Phosphoshift measures activation of RAF signal transduction by detecting the phosphorylation of MEK1/2 in cells unstimulated or stimulated using IL3, a specific activator of the RAF signalling pathway in normal monocytes 2 Median PFS: 3 mo (95%CI 2 10.7); RR: 1/22 (5%) Improved PFS in five patients with an increase in pshift after 7 days of sorafenib vs. those who did not (14.9 months vs 2.8 months; p=0.047). However, pshift did not add value to toxicity-based dosetitration. 1 Quintela-Fandino M et al. BJC 2013;108(6):1298-305) 2 Yagisawa et al Exp Hematol 27: 1063 1076.

Sorafenib: Sorafenib and bevacizumab combination targeted therapy in advanced NET: A phase II study of Spanish Neuroendocrine Tumour Group (GETNE0801) N=44 patients Histologically-confirmed Measurable advanced NETs Moderately or welldifferentiated NET GEP or lung ECOG PS 0-2 1 prior chemo Castellano et al Eur J Cancer (2013) 49, 3780 3787 sorafenib 200 mg bid D1-5 qw bevacizumab 5 mg/kg q2w 1 o endpoint: 6-mo PFS 2 o endpoints: PFS, TTP, OS Median PFS: 12.4 mo Median TTP: 14.5 mo ORR: 9.4% DCR: 95%. 6 mo Contd. (discretionary) All: 91% Carcinoid: 92% pnet: 89% Toxicity was an issue: Grade 3-4 adverse events: 64% Dose adjustments: sorafenib (64%) BVZ (36%) 6 patients (15%) withdrew due to adverse events

Pazopanib small molecule inhibitor of the VEGFR-1, -2, and -3, PDGF-α, PDGF-β, and c-kit tyrosine kinases A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC) Eligibility criteria Patients with either carcinoid or pnet G1-G2 ECOG PS 0-1 Stable dose of depot octreotide (LAR) for 2 months No prior VEGF pathway inhibitor treatment 1 prior cytotoxic 2-cohort, 2-stage design N=51 Stratified by cohort Carcinoid: n=20 Pancreatic: n=31 Pazopanib 800 mg PO QD + Octreotide at their prior dose level Efficacy variables: tumour response, toxicity, and survival Adverse Events Grade 3 4 toxicities were relatively rare and included (%): hypertension (14), fatigue (10), neutropenia (8), diarrhoea (6), elevated ALT (6), elevated AST (6), hypertriglyceridaemia (6), nausea (4) Phan AT, et al. J Clin Oncol 2010;28:15S[Abstract 4001]

Pazopanib: A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC) RECIST best protocol response: ITT population Parameter Overall (N=51)* Carcinoid (n=20) Pancreatic NET (n=31) PR, n (%) 6 (12%) 0 (0%) 6 (19%) SD, n (%) 35 (69%) 14 (70%) 21 (68%) PD, n (%) 6 (12%) 3 (15%) 3 (10%) Unknown 4 (8%) 3 (15%) 1 (3%) PFS 12.7 mo 11.7 mo Treatment with pazopanib and octreotide is feasible Tumor regression in patients with pnet Encouraging PFS durations in both carcinoid and pnet patients Phan AT, et al. J Clin Oncol 2010;28:15S[Abstract 4001]

PAZONET Pazopanib as single agent in advanced/metastatic GEP NETs Design: Multicentre, open-label study evaluating pazopanib as a single agent in progressive advanced/metastatic GEP NETs patients who have failed chemotherapy, SSA or molecular targeted therapies Patients with well differentiated GEP-NET; ECOG performance status 0-1; life expectancy > 3 months Sponsor: GETNE Open to pnet and non-pnet Heterogeneous prior therapies N=44* N=17 pnet Phase 2 Pazopanib 800 mg (2x400mg) qd Null hypothesis CBR = 50% in favour of CBR = 70% if a total of 28 or more subjects out of 44 experience clinical benefit Primary endpoint: CBR (CR+PR+SD) Secondary endpoints: PFS, ORR, DoR, TTR, safety, biomarkers assessment Key Implications: Single-arm study exploring the activity of pazopanib (an oral, potent multi-target tyrosine kinase inhibitor VEGFR-1, -2, and -3, PDGFR-α and β, and c-kit) The threshold of activity was reached to warrant further investigation; efficacy needs to be confirmed in a prospective phase 3 study

PAZONET Pazopanib as single agent in advanced/metastatic GEP NETs Key Results: Clinical benefit (6-mo PFS) was achieved among 36 patients (SD 33 patients, PR 3 patients) = 85.4% No patient achieved CR, while 6 patients were found to have PD Median PFS: 10 months 1 Pazopanib might be efficacious in patients with refractory NETs Sum of the longest diameter of target lesions decreased over 10% among 32.5% of patients 2 (95%CI: 4.8-14.1) P =.722 (95%CI: 11.3 13.5) (95%CI: 0.0-15.3) (95%CI: 8.8-10.1) (95%CI: 1.3-6.8) Progression free survival in months 3 Progression free survival (in months) by 3 subgroups (P =.040) 1. Grande E. Poster presented at: European Society for Medical Oncology (ESMO); September 28-October 02, 2012; Vienna, Austria. 2. Pulido EG., et al. Poster presented at: American Society of Clinical Oncology (ASCO); June 1-5, 2012; Chicago; IL, USA 3. Capdevila J., et al. Poster presented at: European Cancer Congress (ECC); September 27 October 1, 2013; Amsterdam, Netherlands 58

Pazopanib progressive carcinoid tumours Design: Randomised, double-blind, placebo-controlled, crossover study assessing the efficacy of pazopanib Patients with progressive carcinoid tumour, low/or intermediate grade NET, locally unresectable or metastatic CT, or progressive disease N=165 Phase 2 RANDOMISATION Pazopanib HCL orally every 28 days Placebo orally every 28 days Primary endpoint: PFS (RECIST) Sponsor: NCI Disease progression Cross-over from one arm to another Secondary endpoints: OS, OR, QoL, DoR, TTR Key Exclusion Criteria: Prior treatment with an inhibitor of VEGF or VEGFR Concurrent condition resulting in immune compromise, CNS metastases, GI abnormalities, uncontrolled BP, symptomatic congestive heart failure Pazopanib hydrochloride in treating patients with progressive carcinoid tumours. Available at: http://clinicaltrials.gov/ct2/show/nct01841736 Study Status: Ongoing (recruiting) Estimated Primary Completion: Dec, 2016

AXITINIB Effect of increasing concentrations of anticancer therapeutic axitinib (targeting VEGFR1 3, PDGFRA-B, and KIT) on QGP-1 Pancreatic Endocrine Tumour cell growth

Design: Axitinib Octreotide LAR plus axitinib vs. placebo in non-pancreatic NET Randomised, double-blind, efficacy study to compare octreotide LAR in combination with axitinib vs. placebo Patients with progressive, advanced, well-differentiated NET of non-pancreatic origin, Ki-67 index < 20%; ECOG status: 0-2 N=80 Phase 2 RANDOMISATION Axitinib: orally, 5mg, bid plus Octreotide LAR: IM 30mg, single injection every 28 days Placebo: orally, bid plus Octreotide LAR: IM 30mg, single injection every 28 days Primary endpoint: PFS (RECIST) Sponsor: Grupo Español GETNE Secondary endpoints: OS, ORR, Safety Key Implications: Key Exclusion Criteria: Prior VEGF or VEGFR-targeted therapy Major surgery in <4 weeks or radiation therapy <2 weeks Concomitant CYP3A4 inhibitors/inducers, or oral vitamin K antagonists NETs are known to be highly vascular; this randomised phase 2 study will explore the activity of axitinib (a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2 and VEGFR-3) in non-pancreatic, well-differentiated NETs Available at: http://clinicaltrials.gov/ct2/show/nct01744249

A Phase II Study of Axitinib in Advanced Carcinoid Tumors Strosberg, Lee Moffitt Cancer Centre Axitinib: Eligibility criteria G1-G2 non-pnet aerodigestive NET, UKP and rare subtypes Measurable disease PD within 12 months Prior SSA mandated in mid-gut patients ECOG PS 0-2 N=30 Axitinib 5mg bd Primary endpoint: PFS (RECIST) Secondary endpoints: RR, OS, TTF, AEs Clinicaltrials.gov NCT01435122

CABOZANTINIB

In RIP-Tag2 model 1, XL184: Cabozantinib Pre-clinical Eliminated approximately 80% of the tumour vasculature Reduced pericytes and empty basement membrane sleeves Caused widespread intra-tumoural hypoxia and tumour cell apoptosis Slowed regrowth of the tumour vasculature after drug withdrawal. Decreased invasiveness of primary tumours and reduced metastasis Effect of VEGR-blockade amplified 1,2 1. You et al Cancer Res; 71(14); 4758 68 2. Sennino et al Cancer Discov. Mar 2012; 2(3): 270 287.

Cabozantinib inhibits VEGFRs, MET, RET and c-kit An Open-Label, Phase II Study of Cabozantinib (XL184) in Advanced Pancreatic Neuroendocrine and Carcinoid Tumors Massachusetts General Eligibility criteria Well- Moddifferentiated Measurable disease (RECIST) PD within previous 12 months SSA allowed (if stable 2 months ECOG PS 0-1 N=70, parallel cohorts, non-randomised pnet carcinoid Cabozantinib (XL184) 60mg qd Primary endpoint: RR (RECIST) Secondary endpoints: OS, AEs, correlates of response Faris et al ASCO 2014 abstr TPS4157 Clinicaltrials.gov NCT01466036

Korean study Phase II N=37 (Pancreas 12) (CRC 8) (others 17) G1 (8) G2 (16) G3 (13) Primary end-point: response rate 18.9% (24.3% by independent review) Ahn et al BJC 2013;109, 1414 1419

Summary Somatostatin analogues remain the cornerstone for treatment of functional tumours Anti-proliferative effects demonstrated in pre-clinical studies Retrospective / prospective studies suggest effect on tumour progression Octreotide LAR delays time to disease progression but not in all patients CLARINET and COOPERATE-2 will enhance our understanding in a wider population Combination studies may explore any additive / synergistic effects

Angiogenesis inhibitors Agent (s) Target (s) N Tumor ORR, % Outcomes Comments Bevacizumab + octreotide 1 VEGF 22 Carcinoid 18 16.5 months (PFS) 41 Carcinoid 2 10.2 months (TTP) VEGFR, PDGFR, RET, FLT3 Sunitinib 2 66 Pancreatic NET 17 7.7 months (TTP) Sorafenib 3 VEGFR, PDGF, 50 Carcinoid 7 8 months (PFS) Raf 43 Pancreatic NET 17 12 months (PFS) Vatalanib 4 VEGFR, PDGFR 11 GEP NET 0 Not reported Ongoing Pazopanib 5 Motesanib 6 VEGFR, PDGFR, VEGFR, PDGFR, RET 30 30 Carcinoid Pancreatic NET Ongoing 44 LGNET Suspended Atiprimod 7 Unclear 25 LGNET 0 Completed Bevacizumab + VEGF 31 Carcinoid 0 Ongoing 2-methoxyestradiol 8 Sunitinib 9 VEGFR, PDGFR, 74 Pancreatic NET 11.1 months (PFS) Terminated RET, FLT3 ORR = overall response rate; PDGF = platelet-derived growth factor; PDGFR = PDGF receptor; LGNET = low-grade NET. 1. Yao JC, et al. J Clin Oncol 2008:26;1316-23. 2. Kulke MH, et al. J Clin Oncol 2008:26;3403-10. 3. Hobday TJ, et al. J Clini Oncol 2007;25:[abstract 4504]. 4. Anthony L, et al. J Clin Oncol 2008;26:[abstract 14624]. 5. NCT00454363. Available from www.clinicaltrial.gov. 6. NCT00427349. Available from www.clinicaltrial.gov. 7. Sung MW, et al. J Clin Oncol 2008;26:[abstract 4611]. 8. NCT00328497. Available from www.clinicaltrial.gov. 9. Raymond E, et al. Oral presentation at the WCGOC. 2009:[abstr O-0013].

ESMO practice guidelines Öberg et al Annals of Oncology 23 (Supplement 7): vii124 vii130, 2012

RADIANT-2 Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome