Introduction to NETs NETs arise from cells which produce and secrete hormones Most NETs are slow growing and malignant, with metastatic potential Common sites of origin are: GI tract Lungs Pancreas 2
Definitions: Classification, Grade, and Stage Classification = origin, tumor characteristics, behavior Different NET classification systems (WHO, ENET, AJCC) take into consideration different tumor characteristics Grade = inherent biological aggressiveness1 For example: low-grade malignant, intermediate-grade malignant, high-grade malignant Prognostic; may be independent from tumor stage Stage = extent of disease2 For example, organ confined, locally invasive, metastatic, etc. Prognostic; may be independent from tumour grade1. Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-272. Rindi G, et al. Virchows Arch. 2007;451:757-762. 3
ClassificationTraditional Method NETs have been traditionally classified as foregut, midgut, or hindgut, depending on site of origin Replaced by new tumor-based classification method developed by World Health Organization (WHO) 4
ClassificationWorld Health Organization MethodWHO classification defines NETs by degree of tumor differentiation,with specific clinicopathological featuresThe WHO classification system is basedon the following criteria: Biological behavior (malignancy) Metastases Ki-67 index Angioinvasion Tumor size Histological differentiation Hormonal syndrome 5
WHO Classification: NET Grouped By Prognostic Factors Prognosis of Patients With NET Good Poor a pancreatic NETStrosberg JR, et al. GI Cancer Res. 2008;2:113-125.Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-27. 6
WHO Classification for NET Neuroendocrine Tumours Malignant Potential Site of Origin •Benign •GI tract •Benign or low •Pancreas Functional Activity malignant potential •Functioning •Lungs (uncertain) •Non-Functioning •Thyroid •Low malignant •Pituitary potential •Others •Highly malignant 7Ong SL, et al. Pancreatology. 2009;9:583-600.
The Pancreas Is the Most Common Primary Location of NET Breakdown in Middle East & Asia Pacific RegionBile duct and gallbladder 3%Omentum/abdominal lining 1%Rectum 1%Ovary 1%Lung 1% Liver 4% Stomach 6% Hwang T, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C48.
Potential Reasons for Increased Incidence and Prevalence in NET• Exact reasons are unknown but may include: – Potential underdiagnoses and underreporting in the past – Improved diagnostic techniques – Increased awareness of NET in the community 9
GI NETs Clinical PresentationClinical presentation of GI NETs varies widely Often discovered incidentallySymptoms due to: Mechanical bulk Fibrosis Secretion of various hormonesSerotonin is most commonsubstance secreted from GI NET Serotonin-producing GI NET (ileum) Serotonin release can cause carcinoid syndrome 10
GI NETs Carcinoid Syndrome Symptoms of carcinoid syndrome include: Hypotension Flushing Heart disease Rapid heart beat Wheezing DiarrheaCarcinoid syndrome is associated with metastatic disease 11
Pancreatic NETs OverviewpNETs are rare, slow-growingneoplasms Symptoms from excess hormone production or mechanical problems 6.4% of all NETs are found in pancreasIncidence rate of 0.4 cases per100,000 persons Incidence is increasingpNETs may or may not havesecretory symptoms Secretory symptoms related to specific hormones Tumors (nonfunctional) may secrete peptides but cause no clinical symptoms 12
Pancreatic NETs Types Islet cell Predominant hormone Malignant Tumor type produced potentialGastrinoma Gamma Gastrin Very highInsulinoma Beta Insulin LowGlucagonoma Alpha Glucagon Very highVIPoma Delta Vasoactive intestinal peptide HighSomatostatinoma Delta Somatostatin Very highPPoma PP cells Pancreatic polypeptide Very highRelative frequency: Asymptomatic >Insulinoma > Gastrinoma >Glucagonoma > VIPomas > Somatostatinoma > Others 13
Pancreatic NETsClinical Presentation—Asymptomatic pNETs Tumors without secretory symptoms are not associated with a hormonal syndrome Often found incidentally Patients present late with large malignancies or advanced disease Symptoms due to tumor growth or spread Abdominal pain Jaundice Diarrhea Indigestion Weight loss 14
Natural History of Neuroendocrine Tumours Estimated time to diagnosis: 5 to 7 years Death Diarrhea * Vague abdominal symptoms Flushing * Metastases Primary tumour growth 1 2 3 4 5 6 7 8 9 Time, years *Symptoms of carcinoid syndromeVinik A, et al. Pancreas. 2009 Nov;38(8):876-89 15
Nonspecific Symptoms Are Common to Multiple Diagnoses Menopause Functional Bowel Disease Symptoms Food Allergy • Sweating • Flushing Irritable Bowel • Diarrhea Syndrome • Intermittent abdominal pain Neurosis • Hypoglycemia • Confusion • Bronchoconstriction • Dyspepsia • GI bleeding Alcoholism NET • Cardiac disease Peptic Ulcer Asthma Thyrotoxicosis AnxietyAggarwal G, et al. Cleve Clin J Med. 2008;75(12):849-855. 16
Importance of Raising the Index of Suspicion Incidence of NET is increasing More prevalent than other cancers (ie, stomach, pancreas, esophagus) Associations between these symptoms suggest the presence of NET over more common ailments Flushing with NET is unrelated to time or day, warmth, or perspiration Hormone production differs from menopause, which is a typical misdiagnosis Elevated chromogranin A (CgA) is the generally accepted marker for NET 80% to 100% of NET, regardless of symptoms, secrete CgA 17Peracchi M, et al. Eur J Endocrinol. 2003;148(1):39-43.
Systematic Approach to Diagnosing NET Is Needed History and physical exam Biochemical markers (serum, tissue, urine) 1 Serum Tissue Urinary Imaging2 Computed tomography scan (CT)/ Magnetic Resonance Imaging (MRI) Nuclear Imaging Endoscopic ultrasound (pNET only)1. Ferolla P, et al. J Endocrinol Invest. 2008;31(3):277-286. 182. Barakat MT, et al. Endocr Rel Cancer. 2004;11(1):1-18.
General NET Treatment Goals Depending on the results obtained from a workup, a patient’s NET is classified as local, regional, or advanced. Treatment goals should be curative where possible, with the use of pharmacological management as necessary. General Treatment Goals: Local Regional NET The treatment goal for localized NETs is curative, which is most often accomplished with surgery. Advanced NET The treatment goal for metastatic tumors is also curative surgery if possible, followed by pharmacological treatment.
Current Systemic Treatment Options for Patients With Advanced NETs Somatostatin analogues Interferon-alfa Chemotherapy Peptide receptor–targeted therapy Molecular-targeted therapies
Pharmacological Treatment of NET Several types: Somatostatin analogues Currently approved for the relief of certain symptoms associated with symptomatic (functional) GI NETs and pNETs Cytotoxic therapy GI and Lung NETs: An option when no other options are feasible because of the poor efficacy and toxicity. Single-agent and combination therapies with doxorubicin, 5-FU, dacarbazine, actinomycin-D, cisplatin, alkylating agents, etoposide, streptozotocin, and carboplatin have resulted in response rates from 20-50%. pNETs: Systemic chemotherapy is recommended for patients with unresectable liver or lung metastases. Trials using doxorubicin, streptozocin, 5-FU, temozolomide, and dacarbazine have established cytotoxic effects in pNETs. Biological Treatment Interferon Hormone-like proteins normally made by white blood cells to help the immune system fight infections Sometimes helpful in shrinking or slowing growth of advanced NETs and improving symptoms of carcinoid syndrome
Pharmacological Treatment of NET (Continued) Several types: Targeted Therapies Designed to attack some specific aspect of cancer cells A number of investigational therapies have shown preliminary evidence of activity in patients with advanced NETs Targeted Therapies: mTOR Inhibitors everolimus (AFINITOR) Tyrosine Kinase Inhibitors sunitinib, sorafenib VEGF Inhibitors bevacizumab Other Agents Pasireotide, a multiligand somatstatin analogue, is currently in phase III development for NET
PathophysiologySignificance of Somatostatin Signaling Somatostatin (SST) receptors are highly expressed on the surface of GI NETs More than 80% of all NETs express SST receptors Overexpression provides basis for regulation by SST SST receptor activation inhibits secretory and proliferative activity 27
Octreotide May Have a Direct Antitumour Effect via sst2 and sst5 sst2 sst2 sst5 • sst2 and sst5 both downregulate MAPK G protein PI3K G protein PDK1 • sst2 binding effects the SHP2 SHP1 Src G protein P13K/Akt/mTOR Akt pathway and SHP1 PTPŋ SHP1 ↓ cGMP signalling NF-KB GSK3β mTOR MAPK ↓PKG p53 JNK p70S6K • Antiproliferative effect ↑Zac1 p27 also mediated via protein tyrosine phosphatase (PTPase) ↑ Apoptosis ↓ Cell growth modulationFlorio T et al. Front Biosci 2008;13:822–840Grozinsky-Glasberg S et al. Neuroendocrinology 2008;87:168–181Theodoropoulou M et al. Cancer Res 2006;66:1576–1582
PathophysiologySignificance of the mTOR Pathway Alterations in the mTOR pathway result in the development of some NETs 29
Rationale for Combining Everolimus and Octreotide LAR mTOR is a central regulator of ↓secretion IGF-1 ↓ligands VEGF growth, proliferation, metabolism, K+ IGF-1 IGF-1R sst analog sstr1-5 IGF-1R VEGFR and angiogenesis1-3 Ca2· NET have been linked to genetic cAMP PI3K alterations that activate the PTEN ↓signaling mTOR pathway2,3 SHP1 cGMP AKT mTOR TSC1/2 inhibitor Everolimus inhibits mTOR3 Caspase 8 p53 Bax NFcb MAP K NF1 mTOR Octreotide downregulates IGF-1, X X HI F1 VHL Survival Growth and X X a an upstream activator of the proliferation Metabolism Angiogenesis PI3K/AKT/mTOR pathway4 Everolimus + octreotide LAR has shown activity in a phase II trial51. 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.
PROMID: Evaluation of the Antiproliferative Effect of Octreotide LAR 30 mg Phase III randomized, double-blind, placebo-controlled study Patients with midgut NETs Octreotide LAR RANDOMIZATION (1:1) • Treatment naïve 30 mg im Treatment • Histologically confirmed every 28 days until CT/MRI • Locally inoperable documented or metastatic tumour • Well differentiated progression • Measurable (CT/MRI) Placebo im or death • Functioning or non- every 28 days functioning Month 3 6 9 12 15 18 Primary endpoint: Time to tumour progression (blinded central review) Secondary endpoints: objective response rate, survival, quality of life, safetyRinke A et al. J Clin Oncol 2009;27:4656–4663
PROMID Patient Demographics Octreotide LAR Placebo Total 30 mg (n=42) (n=43) (n=85) Median age, years (range) 63.5 (38–79) 61.0 (39–82) 62.0 (38–82) Sex male (%) 47.6 53.5 50.6 female (%) 52.4 46.5 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 (%) 16.7 11.6 14.1 >80 (%) 83.3 88.4 85.9 Carcinoid syndrome* (%) 40.5 37.2 38.8 Resection of primary (%) 69.1 62.8 65.9 Hepatic tumour load 0% 16.7 11.6 14.1 0–10% 59.5 62.8 61.2 10–25% 7.1 4.7 5.9 25–50% 11.9 9.3 10.6 50% 4.8 11.6 8.2 Octreoscan positive (%) 76.2 72.1 74.1 Ki-67 up to 2% (%) 97.6 93.0 95.3 CgA elevated (%) 61.9 69.8 65.9 * not requiring octreotide for symptom controlRinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
Octreotide LAR 30 mg Extends TTP in Patients with Functioning and Non-functioning Tumours Patients with non-functioning tumours Patients with functioning tumours Octreotide LAR 30 mg: 25 pts / 9 events Octreotide LAR 30 mg: 17 pts / 11 events Median TTP 28.8 months Median TTP 14.26 months Placebo: 27 patients / 24 events Placebo: 16 patients / 14 events 1 1 Median TTP 5.91 months Median TTP 5.45 monthsProportion without progression Proportion without progression 0.75 0.75 0.5 0.5 0.25 0.25 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Time (months) Time (months) P=0.0008; HR=0.25 [95% CI: 0.10–0.59] P=0.0007; HR=0.23 [95% CI: 0.09–0.57] Based on the per protocol analysisArnold R. Abst #4508 presented at ASCO 2009, Orlando FLRinke A et al. J Clin Oncol 2009;27:4656–4663
Phase III Randomized Trial of Everolimus (RAD001) vs Placebo in Advanced Pancreatic NET (RADIANT-3) James Yao1, Manisha Shah2, Tetsuhide Ito3, Catherine Lombard-Bohas4, Edward Wolin5, Eric Van Cutsem6, David Lebwohl7, Sakina Hoosen7, Carolin Sachs8, Jeremie Lincy8, Timothy Hobday9 and Kjell Öberg10 for the RADIANT-3 study group
RADIANT-3 Study Design Phase III Double Blind Placebo Controlled Trial Everolimus 10 mg/d + R best supportive care* Patients with A advanced pNET, n = 207 N N = 410 D 1:1 Treatment Stratified by: O until disease •WHO PS M Crossover progression •Prior I Z Placebo + Chemotherapy E best supportive care* n = 203 Multi-phasic CT or MRI performed every 12 weeks Primary endpoint: Secondary endpoints: • PFS (RECIST) • Response, OS, biomarkers, safety, and PK* Concurrent somatostatin analogs allowedRandomization August 2007 - May 2009Yao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
PFS by Central Review* Kaplan-Meier medians PFS Everolimus: 11.4 months Placebo: 5.4 months Hazard ratio = 0.34; 95% CI [0.26-0.44] Percentage event-free P-value: <0.0001 No. of patients still at risk Everolimus Placebo * Independent adjudicated central review committee • P-value obtained from stratified one-sided log rank test • Hazard ratio is obtained from stratified unadjusted Cox modelYao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
Overall Survival Everolimus 10mg Placebo N = 207 N = 203 No. of events – n (%) 51 (24.6%) 50 (24.6%) HR = 1.05; 95% CI [0.71-1.55]; P = 0.594 No. censored – n (%) 156 (75.4%) 153 (75.4%) Kaplan-Meier estimates [95% CI] at: 3 months 97.1 [93.6-98.7] 98.5 [95.5-99.5] 6 months 93.1 [88.7-95.9] 91.6 [86.8-94.7] 12 months 82.3 [76.0-87.0] 82.6 [76.5-87.3] 18 months 73.1 [65.1-79.6] 73.9 [66.1-80.2] 24 months 57.3 [43.0-69.2] 62.8 [51.1-72.4] 148 placebo patients crossed over to receive everolimus Hazard ratio is obtained from the unadjusted stratified Cox model P-value is obtained from the stratified one-sided log rank testYao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
Summary Everolimus provided a 65% reduction in risk for progression compared to placebo (HR = 0.35, P < 0.0001)• Everolimus therapy resulted in a significant 6.4 month increase in median PFS – 4.6 months to 11.0 months• 18 months PFS rate of 34% vs 9% placebo demonstrates that everolimus provides a durable benefit Disease control rate (CR+PR+SD) was 77.7% with a significant response difference, P < 0.0001 Everolimus showed a consistent benefit in all subgroups Everolimus has an acceptable safety profile
Sunitinib Phase III Trial: SummaryInvestigator, algorithmic, and central analysis of PFS showed a mediandifference in PFS of 5.9 to 7.2 months (HR, 0.32-0.42) favoring sunitinib The increase in PFS was not statistically significant Though there is evidence of a clinically meaningful benefit, the magnitude of this benefit remains unclear due to the study being terminated early These PFS results may be an overestimate because of early looks at the data and premature study terminationThe FDA did an additional analysis, and found a median PFS of 10.2 monthsfor sunitinib and 5.4 months for placebo; these data were used in the Sutentprescribing informationThere was no statistically significant improvement in OS(43% event rate; 69% crossover)There was an increased risk for serious AEs associated with sunitinib,including 2 deaths from cardiac failureMedian exposure to treatment and follow up were 4.6 months and 10.2months in the sunitinib arm and 3.7 months and 5.4 months in the placeboarm 40
SummaryThe sunitinib trial and RADIANT-3 are both phase III,randomized, double-blind studies that assessed theeffects of treatment on PFS in patients with advancedpNET However, the trials differ substantially in design, patient population, and study conduct and, therefore, can not be directly compared 42