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Neuroendocrine Tumors in 2016

This document discusses neuroendocrine tumors (NETs). It begins with disclosing the speaker's relationships with various pharmaceutical companies. It then outlines some of the challenges in diagnosing and treating NETs, which are rare tumors that can occur in many locations. The document discusses the increasing incidence of NETs and covers their pathology, classification, biomarkers, and imaging. It notes that metastatic disease is common at initial presentation for many patients. Finally, it briefly discusses the goals and options for therapy in advanced NETs, including symptom control and cytotoxic therapy.

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NEUROENDOCRINE TUMORS: Mohamed Abdulla M.D. Prof. of Clinical Oncology Cairo University Asyut Clinical Oncology Annual Conference NOVARTIS Symposium 23/02/2016 “Capture a MACRO Portrait”
Disclosures: • Amgen • Merck Serono • Janssen Cilag • Astra Zeneca • Pfizer • Astellas. • Hoffman La Roche • Novartis
Challenges: • Rare • One Cell of Origin  Many Locations  Many Faces. • +/- Hormonal Syndromes. • Problems of Diagnosis. 1. Clinically VAGUE. 2. TISSUE DIAGNOSIS. • Delayed Onset of Diagnosis  Advanced Disease. • Lacking of Response to Available Treatment Options A HASSLE & WASTE OF RESOURCES OR REAL UNDERESTIMATED PROBLEM?
Origin: Neuropeptides Catecholamines Hormonal Syndromes Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40:1.
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 0.00 1.00 2.00 3.00 4.00 5.00 6.00 0 100 200 300 400 500 600 Incidenceper100,000-NETs Incidenceper100,000–Allmalignantneoplasms All malignant neoplasm Neuroendocrine tumors Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. Increasing Incidence Plateau 1.09 5.25
Incidence of NETs Is Increasing* 8 8 SEER = Surveillance, Epidemiology, and End Results (for malignant NETs) *Approximate 5-fold increase between 1975 and 2004 Approximate 7-fold increase also evident in Norwegian registry IncidencePer100,000 1.40 Year NET Site 1.20 1.00 0.80 0.60 0.40 0.20 0 Lung Colon Small intestine Rectum Pancreas Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.
Colon Neuroendocrine Stomach 29-year limited duration prevalence analyses based on SEER Pancreas Esophagus Hepatobiliary 0 100 1,100 NET Prevalence in the US, 2004 1,200 Median survival (1988 – 2004)103,312 cases (35/100,000) No.ofcases (thousands) Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. NETs Are the 2nd-Most Prevalent Gastrointestinal Tumor: • Localized • Regional • Distant 203 months 114 months 39 months
NET: Demographics: Lepage C, et al. Gut. 2004;53(4):549-553.
descendin g colon (<1%) sigmoid colon (- 12%) Primary Tumor Localizations est. % of all NEN thymus bronchus esophagus stomach duodenum pancreas jejunum/ileum cecum appendix colon rectum <1 15 <1 15 4 15 15 2 15 1 10 thymus (1%) bronchus (-15%) esophagus (<1%) pancreas (-15%) duodenum (-4%) ascending colon (- 1%) jejunum (-5%) ileum (-10%) cecum (-2%) appendix (-15%) rectum (-10%) stomach (-15%) Pape UF, et al. Gastroenterol up2date. 2011;7:313- 339.
Hormone Hypersecretion Syndromes (= Functioning NET) Calcitonin Somatostatinoma Cushing syndrome Atypical carcinoid syndrome Verner Morrison syndrome (VIPom) Glucagonoma Gastrinoma Insulinoma Carcinoid syndrome 0 20 40 60 80 100 120 140 160 180 200 220 240 244 158 76 16 8 5 6 2 1 Begum N, et al. Zentralbl Chir. 2014;139(3):276-283. Functioning: 39.5% (553) Non-functioning: 60.0% (836) Unclear: 0.5% (11)
NE-cell Enterocyte Enterocyte Enterocyte Enterocyte Pathogenesis of Carcinoid: Rindi G, Wiedenmann B. Nat Rev Endocrinol. 2011;8(1):54-64
Pathogenesis of Carcinoid: TRYPTOPHAN METABOLISM NORMAL NET 1% SEROTONIN 70% SEROTONIN FOREGUT MIDGUT HINDGUT Aromatic L- Amino Acid Decarboxylase
Pathogenesis of Carcinoid: Marc Díez, Alexandre Teulé, Ramon Salazar.Ann Gastroenterol 2013; 26 (1): 29-36
Pathogenesis of Carcinoid: Somatostatin: The Natural Defense Mechanism: SOMATOSTATIN Somatostatin Receptors Short Lived Bio-availability
Niederle MD, et al. Endocr Relat Cancer. 2010;17(4):909-918. Biologicalbehavior Malignant Uncertain Benign NET: Not all the same:
Key Issues in The Management: 1. How do we define the disease? Nomenclature, Classification & Pathology. 2. Who needs treatment and when? Patient Selection. 3. Which treatment and in what sequence? Treatments. 4. What is the role of combined biologics, somatostatin analogues, cytotoxics and biomarkers? Unanswered Questions.
1.How do we define the disease? Nomenclature, Classification and Pathology
Evolution of Terminology & Classification: Historic Evolution: 1907 1963 1970 1980 1995 Carcinoid Williams & Sandler Soga & Tazawa Histologic WHO Granular Stain Techniques Capella Size & Invasion • Benign. • Benign or Low Grade Malignant. • Low Grade Malignant. • High Grade Malignant. No Prognostic or Predictive Validation
H.E. MIB-1/Ki67 synaptophysin CgA Neuroendocrine Neoplasms
Evolution of Terminology & Classification: Histopathologic Differentiation: Well Differentiated Poorly Differentiated
Evolution of Terminology & Classification: AJCC Criteria of Grading: Grade Mitotic Count (per 10 HPF) Ki 67 Index (%) G1 < 2 < 2 G2 2 – 20 3 – 20 G3 > 20 > 20 AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.
Evolution of Terminology & Classification: Correlation of Tumor Grade With Survival: 1. Rindi G, Klöppel G, Alhman H, et al. Virchows Arch. 2006;449:395-401. 2. Rindi G, Klöppel G, Couvelard A, et al. Virchows Arch. 2007;451:757-762. 3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer. 2008;113:256-265. 0 50 100 150 200 250 Survival Time (mo) 0.0 0.2 0.4 0.6 0.8 1.0 CumulativeSurvival G1 G2 G3 G1 vs G2 G1 vs G3 G2 vs G3 P=0.040 P<0.001 P<0.001 N=193
Scarpa A, et al. Mod Pathol. 2010;23(6):824- 833. < 2% 15% 75% Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097. Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798- 7803. Vilar E, et al. Endocr Relat Cancer. 2007;14(2):221- 232. Prognostic Influence of Ki67-Labelling
Evolution of Terminology & Classification: Correlation of TNM Staging With Survival: 26 26 La Rosa S, Klersy C, Uccella S, et al. Hum Pathol. 2009;40:30-40. Patients With Well-Differentiated Pancreatic NET Stage I P<0.001 ProportionAlive Stage II Stage III Stage IV I (n = 44) II (n = 44) III (n = 34) IV (n = 33) Time (mo) 0.00 0.25 0.50 0.75 1.00 0 48 96 144 192 240
Evolution of Terminology & Classification: NETs Are Often Diagnosed Late: Vinik AI, Silva MP, Woltering EA, et al. Pancreas. 2009;38:876-889. 1 2 3 4 5 6 7 8 9 Time (yr) Primary tumour growth Metastases Flushing Diarrhea Death Vague abdominal symptoms Estimated time to diagnosis: 5 to 7 yr * * *Symptoms of carcinoid syndrome
Evolution of Terminology & Classification: Metastatic Disease Is Common at Presentation: Localized Metastatic 50% 27% 23% Distant metastases Regional spread Data from an analysis of 28,515 cases of NET identified in the SEER registries Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072. *These data are of the cases in which stage was reported. 20% of cases did not provide disease stage information
Pathology Report of NETs • Define location and tumor type based on WHO classification • Define tumor grade (including Ki-67 proliferative index) • Describe the presence of additional histologic features (multicentric disease, non-ischemic tumor necrosis, vascular or perineural invasion) • Assess the TNM stage • Define the resection margins • Define the hormonal production, if any • Upon request, assess prognostic or predictive factors useful for target therapy (eg, somatostatin receptors, mTOR pathway molecules, other target enzymes, …) Klimstra D, et al. Am J Surg Pathol. 2010;34(3):300-313.
2. Role of Biomarkers & Imaging:
Pan-neuroendocrine markers Cytosolic NSE, PGP 9.5 Related to secretory granules Chromogranin Related to synaptic vesicles Synaptophysin, VMAT Intermediate filaments NF, CK HMW Adhesion molecules N-CAM Immunohistochemical NE markers:
 Chromogranin A* (in 70%-90% increased in metast. NET)  Pancreatic Polypeptide, PP (in 40%-55 % elevated);  a-HCG, β-HCG (in ~ 30% elevated)  Neuron specific enolase (NSE) (in ~33% elevated) *The height of Chromogranin A level correlates with tumor load, an increase over time indicates tumor progression Circulating Tumor Markers:
CgA correlates with hepatic tumor load Heigher CgA levels indicate lower survival Arnold R, et al. Clin Gastroenterol Hepatol. 2008;6(7):820-827 Prognostic Value of CgA:
HR = 0.25 95% CI: 0.13-0.51 P = .00004 Median PFS Early response = 13.3 mos. No early response = 7.5 mos. 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 HR = 0.25 95% CI: 0.10-0.58 P = .00062 CgA NSE Median PFS Early response = 8.6 mos. No early response = 2.9 mos. PFS(%) 0 20 40 60 80 100 0 20 40 60 80 100 Time Since Study Start, months Time Since Study Start, months Pts at Risk Pts at Risk Resp. 33 29 26 19 12 5 3 2 0 Resp. 28 23 16 9 6 3 1 0 0 Nonresp 38 26 12 5 1 1 0 0 0 Nonresp. 11 5 2 0 0 0 0 0 0 Yao JC, et al. J Clin Oncol. 2010;28(1):69-76. RADIANT-1 (Stratum I) Predictive Value of Biomarkers: PFS by Early CgA and NSE Responses:
Modlin IM, et al. Ann Surg Oncol. 2010;17(9):2427-2443. PPI Chronic Atrophic Gastritis PPI H2RAs Small cell lung cancer Prostate cancer Breast cancer Ovary Cancer Chronic atrophic gastritis Pancreatitis Inflammatory bowel disease Irritable bowel syndrome Liver cirrhosis Chronic hepatitis Colon cancer HCC Pancreatic adenocarcinoma Pheochromocytoma Hyperparathyroidism Pituituary tumors Medullary thyroid carcinoma Hyperthyroidism CgA ENDOCRINE DISEASE GASTRO- INTESTINAL DISORDERS NON-GI CANCER Arterial hypertension Cardiac insufficiency Acute coronary syndrome Giant cell arteritis CARDIOVASCULAR DISEASE Systemic rheumatoid arthritis Systemic inflammatory response syndrome Chronic bronchitis Airway obstruction in smokers INFLAMMATORY DISEASES Renal Insufficiency RENAL DISORDERS DRUGS Causes of Chromogranin A Elevation:
Diagnosis: Imaging Primary Tumor/Tumor Spread:  Whole body Screening & Staging  Endocrine Pancreatic tumor < 1cm  Routine imaging  Primary tumour Screening & Staging (optional)  Octreoscan (111Indium-DTPA- Octreotide)/ SPECT: 1. choice  Endoscopic ultrasonography  ultrasonography of the liver  CT (+ angiography), MRI  Positron emission tomography (PET) with 11C-5 HTP,11C-L-dopa or 18F-FDG  SMS-R-PET: 68Gallium-DOTATOC- PET  PET/CT ENETS-Guidelines 2011
3. Therapy for Advanced Disease “Symptom Control & Cytotoxic Therapy”
Therapy of NETs Three principles • Control of hormonal symptoms • Control of tumor growth • Improvement of survival? Symptomatic therapy Surgical therapy Antiproliferative therapy • Cure • Debulking • Treatment / Prevention of complications
Resection of primary tumor in distant metastatic disease? 249 primary resected, MS = 7.4 y Hellman et al, 2002 Givi et al, 2006 Ahmed et al, 2009 Rinke et al 2009 Resection of primary tumor (intestine) and impact on prognosis
Survival after resection of liver metastases Consenus Conference, London 2012 Frilling et al, 2014, *Sarmiento et al 2003, Elias et al 2003, Glazer et al 2010, Mayo et al 2010 Limitations Complete resection in 20–57% Recurrence in up to 94% after 5 years* No randomized trials
Therapy of GEP-NETs: Shifting From Symptom Management to Targeting Tumors Somatostatin analogues Symptomatic therapy (carcinoid syndrome) Control of tumor growth
Possible Mechanisms for Antiproliferative Activities of SSAs Antiproliferative effect of SSA Direct antiproliferative effect Indirect antiproliferative effect Binding to the somatostatin receptor on tumor cells Systemic effect Inhibition of cell cycle Inhibition of growth factor effects Pro- apoptotic effect Inhibition of growth factor and trophic hormones Inhibition of angiogenesis Immune system modulation Susini C, et al. Ann Oncol. 2006;17(12):1733-1742.
Somatostatin Receptors (SSTR) Are Expressed by the Majority of NETs • SSTR2 is most prevalent in GEP-NETs and induces inhibitory effects on hormone secretion and proliferation in NETs • Somatostatin is effective in controlling NET-related hormonal symptoms • Clinical use of somatostatin is limited by its short half life Basu B, et al. Endocr Relat Cancer. 2010;17(1):R75-R90. Modlin IM, et al. Aliment Pharmacol Ther. 2010;31(2):169-188. Hofland LJ. J Endocrinol Invest. 2003;26(8 Suppl):8-13. Ferrante E, et al. Endocr Relat Cancer. 2006;13(3):955-962. Prevalence on NET type: SSTR1 SSTR 2 SSTR3 SSTR4 SSTR5 Pancreas 68% 95% 46% 93% 57% Midgut 80% 86% 65% 35% 75% Inhibitory effect: Hormone secretion + + + Proliferation + + + + Induction of apoptosis + +
• Octreotide and lanreotide show high affinity for the SSTR2 and are approved for antisecretory treatment in NETs LAR, long lasting release Susini C, et al. Ann Oncol. 2006;17(12):1733- 1742. Octreotide LAR (10-30 mg / 28 days im) Lanreotide (60-120 mg / 28 days sc) Octreotide (2-3 x 50-500 ug sc / d) Biotherapy of Functional Active NETs With Somatostatin Analogs (SSA) S S a l a g l y ly asn s cys p h e p h e p h e tr p l y s t h r p h e t h r s e r cys D-phe c y s phe l y s c th y r s Octreotide acetate D-trp Thr - ol D-phe c l y s v al c y y s S ty r s Lanreotid e D-trp Thr - NH2 S Somatostatin S S
Phase III Study of Octreotide LAR: PROMID Study: Patients: • Well-differentiated midgut NET • Treatment-naïve • Locally inoperable or metastasized N = 85 Octreotide LAR 30 mg im/28 days Placebo im/28 days Primary endpoint: • Median time to tumour progression Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663. 1:1 R A N D O M I Z E Secondary endpoints: •Objective tumour response rate • Symptom control • Overall survival Treatment until CT/MRI documented tumour progression or death Randomized, Double-blind, Placebo-controlled Study
Octreotide LAR 30 mg Significantly Prolongs TTP: HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumours; TTP = time to progression Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663. Octreotide LAR vs placebo HR=0.34 P=0.000072 [95% CI: 0.20–0.59] Based on conservative ITT analysis ProportionWithout Progression 1.0 .75 .50 .25 0 0 6 12 18 24 30 36 42 Time (mo) 48 54 60 66 72 78 Octreotide LAR (n = 42) Median 14.3 mo Placebo (n = 43) Median 6.0 mo
Octreotide LAR 30 mg Extends TTP in Patients With Functioning and Nonfunctioning Tumours: 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Based on the per-protocol analysis P=0.0008; HR=0.25 (95% CI: 0.10–0.59) ProportionWithoutProgression P=0.0007; HR=0.23 (95% CI: 0.09–0.57) ProportionWithoutProgression Patients with nonfunctioning tumours Patients with functioning tumours Time (mo)Time (mo) Octreotide LAR 30 mg: 17 pts/11 events Median TTP 14.26 mo Placebo: 16 pts/14 events Median TTP 5.45 mo Octreotide LAR 30 mg: 25 pts/9 events Median TTP 28.8 mo Placebo: 27 pts/24 events Median TTP 5.91 mo 1. Arnold R, Müller H, Schade-Brittinger C, et al. J Clin Oncol. 2009;27(suppl):15s. Abstr 4508. 2. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
Octreotide LAR (n=42) Placebo (n=43) Complete response (n) 0 0 Partial response (n) 1 1 Stable disease (n) 28 16 Progressive disease (n) 10 23 Unknown (n) 3 3 Wilcoxon-Mann-Whitney: P=0.0079 Octreotide LAR Achieved Superior Tumor Response at 6 Months (WHO): Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
The PROMID Study: Octreotide LAR in Midgut NETs – What Did We Learn? Lessons Limitations Rinke A, et al. J Clin Oncol. 2009;27(28): 4656-4663. Octreotide LAR shows antitumor effect in: • Midgut tumors • Low hepatic tumor burden (<10%) • Grade 1 tumors The efficacy of SSAs is uncertain in: • Non-midgut tumors • Higher liver tumor burden (<10%) • Grade 2 tumors • Progressive disease Would an antiproliferative effect be replicable, with lanreotide, in a larger and more advanced population with GEP-NETs?
Lanreotide Acetate in NET: • Patient Characteristics: Clarinet Trial: • Well to Moderately differentiated. • Ki 67 < 10% • Pancreas, mid-gut, hind-gut, or Unknown origin. N Engl J Med 2014;371:224-33.
The SYM-NET StudyDESIGNASSESSMENTS A non-interventional cross sectional study to assess SYMptom control in neuroendocrine tumors (NET) Non-interventional, cross-sectional study 273 patients suffering from NET, already treated with lanreotide for at least 3 months and with history of diarrhea due to carcinoid syndrome were enrolled Subject questionnaires Investigator review of medical record Likert scales • Patient satisfaction • Symptom severity • Perception change diarrhea • Feelings about conse- quences on daily life QoL • EORTC C30 • EORTC GI- NET21 Demography Medical history Treatment with lanreotide Diarrhea Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ characteristics • At Tt initiation • Day of visit Other clinical data • At Tt initiation • Day of visit Qol = quality of life
SYM-NET Study – Results and Conclusion Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ • An improvement was observed for the majority of patients in all symptoms – 76 % patient satisfaction with diarrhea control (primary objective) – 73 % patient satisfaction with flushing control – QoL questionnaires showed a high level of activity capacity and low symptoms score • Patient-reported "subjective" information was consistent with investigator’s observation • Confirms in real life setting the satisfactory effect of lanreotide on symptoms of hormonal excess in GEP- NETs
Symptom relief in carcinoid syndrome by Somatostatin analogsSymptomaticresponse(%) 0 25 50 75 100 Octreotide Octreotide LAR Lanreotide Lanreotide slow release / autogel Mean: 74.2 Median: 71 Mean: 77.3 Median: 75 mean: 63.0 median: 63 mean: 67.5 median: 63 Modlin IM, et al. Alimentary Pharmacol Ther. 2010;31:169-88. Studies (n) 11 7 1 7 Patients (n) 261 122 30 185
Objective response rate: <20 % n = 367 STZ, streptozotocin; 5FU, 5-flurouracil; DOX, doxorubicin Moertel CG, et al. Cancer Clin Trials. 1979;2(4):327-334. Engstrom PF, et al. J Clin Oncol. 1984;2(11):1255-1259. Bukowski RM, et al. Cancer. 1987;60(12):2891-2895. Sun W, et al. J Clin Oncol. 2005;23(22):4897-4904. Öberg K, et al. Ann Oncol. 2010;21:v223–v227. Chemotherapy Is Not Effective in NETs Grade 1/ Grade 2 of the Midgut (Carcinoids) Reference Type of tumor Regimen No. of patients Objective response Response duration (months) Median survival (months ) Moertel and Carcinoids 5FU + cyclophosphamide 47 33 – – Hanley STZ + 5FU 42 33 – – Engstrom et al Carcinoids STZ + 5FU 80 22 8 16 DOX 81 21 6.5 12 Bukowski et al Carcinoids STZ + DOX + 5FU + cyclophosphamide STZ + 5FU + 56 9 31 22 – – – 10.8 cyclophosphamide Sun et al Carcinoids DOX + 5FU 25 15.9 4.5 15.7 STZ + 5FU 27 16 5.3 24.3
Chemotherapy for G3 NET: NORDIC Trial: Annals of Oncology 24: 152–160, 2013
Temozolomide in Pancreatic Neuroendocrine Carcinoma Strosberg JR, et al. Cancer 2011;117(2):268-275 Capecitabine Temozolomide every 28 days 750 mg/m2 x 2 x tgl. (days 1– 14) 200 mg/m2 x 1 (days 10–14); n = 30: 22 NF; 2 gastrinoma; 2 insulinoma; 2 VIPoma; 1 glucagonoma; 1 gastrinoma/glucagonoma 70% PR (RECIST ) Median PFS: 18 months Retrospective analysis G3–4 adverse events (12%): anemia, thrombocytopenia, elevation of liver enzymes 100 80 60 40 20 0 –20 –40 –60 –80 –100 Progressive Disease Partial Response
Streptozocin/5-Fu are RE-EMPOWERED in 2015:
Streptozocin/5-Fu are RE-EMPOWERED in 2015: RR & Treatment Outcome:
Streptozocin/5-Fu are RE-EMPOWERED in 2015: Which Subset Got Benefit?
4. Molecular Events &Targeted Therapies.
Molecular Events & Therapeutic Implications: 1. Angiogenesis: vHL Gene OxygenationHypoxia +++ VEGFAngiogenesis PFS 96% 68% Bevacizumab + Octreotid LAR INF + Octreotid LAR Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, Hess K, Ng C, Abbruzzese JL, Ajani JA. J Clin Oncol. 2008;26(8):1316.
Molecular Events & Therapeutic Implications: 2. mTOR Pathway: Mammalian Target of Rapamycin mTORC1 mTORC2 Protein Synthesis Cell Growth Autophagy Altered Metabolism Increased Proliferation Apoptosis Resistance +++ +++ RTK AKT PI3K RAS –RAF MEK
Targeted Drugs in Neuroendocrine Tumors  Novel Somatostatin analogues: Pasireotide (SOM230), chimeric molecules (e.g. Dopastatin)  Others: Tryptophan hydroxylase inhibitor (Telotristat Etiprate, LX1606), IGF-1 R antagonists/ antibodies, HDAC inhibitors etc  Angiogenesis inhibitors: VEGF-Receptor-Tyrosinkinase-Inhibitor PTK787/ZK, Anti-VEGF (Bevacizumab), Endostatin, Thalidomide  Single / multiple tyrosine kinase inhibitors: Imatinib, Gefitinib, Sorafenib, Sunitinib  mTOR Inhibitors: Temsirolimus, Everolimus
Everolimus 10 mg/d + best supportive care1 n = 207 RADIANT-3: Study Design Placebo + best supportive care1 n = 203 Multiphasic CT or MRI performed every 12 weeks Treatment until disease progression Patients with advanced pNET, N = 410 Stratified by: • WHO PS • Prior chemotherapy Crossover 1:1 R A N D O M I S E Phase III, Double-Blind, Placebo-Controlled Trial Primary Endpoint: PFS Secondary Endpoints: OS, ORR, biomarkers, safety, pharmacokinetics (PK) Yao J, Shah M, Ito T, et al. N Engl J Med. 2011;364:514-523. 1:1
RADIANT-3: Baseline Characteristics Everolimus (n = 207) Placebo (n = 203) Median age, years (range) 58 (23-87) 57 (20-82) Male : Female (%) 53 : 47 58 : 42 WHO PS (%) 0 / 1 / 2 67 / 30 / 3 66 / 32 / 3 No. of disease sites(%) 1 25 31 2 41 32 ≥3 34 38 Histologic Grade (%) Well differentiated 82 84 Moderately differentiated 17 15 Unknown 1 1 Prior Treatment (%) Somtatostatin analogues 49 50 Chemotherapy 50 50 Radiotherapy 23 20 Yao J, Shah M, Ito T, et al. N Engl J Med. 2011;364:514-523.
RADIANT-3 PFS by Investigator Review: • P value obtained from stratified 1-sided log-rank test • Hazard ratio is obtained from stratified unadjusted Cox model %Event-free 0 2 4 6 8 10 No. of patients still at risk Kaplan-Meier median PFS Everolimus: Placebo: 11.0 mo 4.6 mo Hazard ratio = 0.35; 95% CI 0.27–0.45 P value: <.0001 PFS rate (18 mos.) Everolimus 34.2% Placebo 8.9% Yao JC, et al. N Engl J Med. 2011;364(6):514- 523. 12 14 16 18 Time (mo) 100 80 Censoring times Everolimus (n/N = 109/207) Placebo (n/N = 165/203) 60 40 20 0 20 22 24 26 28 30
• Everolimus toxicities were similar to those seen in other tumour types • Most frequently reported all-grade treatment-related AEs with everolimus were stomatitis (64%), rash (49%), diarrhea (34%), fatigue (31%), and infections (23%) • Grade 3/4 AEs (≥5%) in the everolimus arm included stomatitis (7%), anemia (6%), and hyperglycemia (5%) Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523. RADIANT-3: Treatment-Related Adverse Events
RADIANT-3: Summary • Everolimus therapy resulted in a statistically and clinically significant 6.4-month increase in median PFS (4.6 months to 11.0 months) • Everolimus provided a 65% reduction in risk for progression compared to placebo (HR = 0.35, P<.0001) • PFS rate at 18 months: 34% everolimus versus 9% placebo demonstrates that everolimus provides a durable benefit • Everolimus has an acceptable safety profile in patients with advanced pNET
RADIANT-2 Study Design: Everolimus 10 mg/day + Octreotide LAR 30 mg/28 days n = 216 Placebo + Octreotide LAR 30 mg/28 days n = 213 Treatment until disease progression R A N D O M I Z E 1:1 Multiphasic CT or MRI performed every 12 wk Crossover Primary endpoint: • PFS (RECIST) Secondary endpoints: • Tumour response, OS, biomarkers, safety, PK Enrollment January 2007–May 2008 Phase III, Double-blind, Placebo-controlled Trial Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8. Patients with advanced NET (N=429) • Advanced low- or intermediate- grade NET • Radiologic progression <12 months • History of secretory symptoms (flushing, diarrhea) • Prior antitumour therapy allowed • WHO PS ≤2
PFS by Central Review:* Time (mo) No. of patients still at risk E + O P + O 216 213 202 202 167 155 129 117 120 106 102 84 81 72 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 1-sided log-rank test • HR is obtained from unadjusted Cox model E + O = everolimus + octreotide LAR P + O = placebo + octreotide LAR 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 PercentageEvent-free Kaplan-Meier median PFS Everolimus + octreotide LAR: 16.4 mo Placebo + octreotide LAR: 11.3 mo HR = 0.77; 95% CI (0.59–1.00) P=0.026 Total events = 223 Censoring times E + O (n/N = 103/216) P + O (n/N = 120/213) Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
Subgroup PFS Analysis: *Independent adjudicated central review HR = everolimus + octreotide/placebo + octreotide Unstratified Cox model was used to obtain HR E + O = everolimus + octreotide LAR P + O = placebo + octreotide LAR Subgroups (N) Central review *(429) Local investigator review (429) Age group <65 yr (286) ≥65 yr (143) Gender Male (221) Female (208) WHO Performance Status WHO = 0 (251) WHO > 0 (176) Tumour histology grade Well-diff. (341) Moderately diff. (68) Primary tumour site Small intestine (224) Lung (44) Colon (28) Other (132) Prior long-acting SSA Yes (339) No (90) Prior chemotherapy Yes (130) No (299) HR Median PFS (mo) E + O P + O 0.77 16.4 11.3 0.78 12.0 8.6 0.78 19.2 13.0 0.75 13.9 11.0 0.85 13.7 13.0 0.73 17.1 11.1 0.67 21.8 13.9 0.81 13.6 8.3 0.74 18.3 13.0 0.82 13.7 7.5 0.77 18.6 14.0 0.72 13.6 5.6 0.39 29.9 13.0 0.77 14.2 11.0 0.81 14.3 11.1 0.63 25.2 13.6 0.70 13.9 8.7 0.78 19.2 12.0 Hazard Ratio Favors E + O Favors P + O 0 10.4 0.8 1.4 Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
Everolimus: Real World Trial:
Everolimus: Real World Trial:
Everolimus: Real World Trial:
Everolimus: Real World Trial: • Med PFS = 12 months • Med OAS = 32 months • Pancreatic = Non Pancreatic
RADIANT-4 Study Design *Based on prognostic level, grouped as: Stratum A (better prognosis)  appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worse prognosis)  lung, stomach, rectum, and colon except caecum. Crossover to open label everolimus after progression in the placebo arm was not allowed prior to the primary analysis. Endpoints: • Primary: PFS (central) • Key Secondary: OS • Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK Patients with well- differentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N = 302) • Absence of active or any history of carcinoid syndrome • Pathologically confirmed advanced disease • Enrolled within 6 months from radiologic progression Everolimus 10 mg/day N = 205 Treated until PD, intolerable AE, or consent withdrawal 2:1 R A N D O M I Z E Placebo N = 97 Stratified by: • Prior SSA treatment (yes vs. no) • Tumor origin (stratum A vs. B)* • WHO PS (0 vs. 1)
Characteristic Everolimus N = 205 Placebo N = 97 Age, median (range) 65 (22 – 86) 60 (24 – 83) Male / female 43% / 57% 55% / 45% WHO performance status 0 / 1 73% / 27% 75% / 25% Race Caucasian 79% 70% Asian 16% 19% Other* 5% 11% Primary tumor site Lung 31% 28% Ileum 23% 25% Rectum 12% 16% Jejunum 8% 6% Stomach 3% 4% Duodenum 4% 2% Colon 2% 3% NET of unknown primary 11% 13% Baseline and Disease Characteristics (1/2) *Included Black.
Characteristic Everolimus N = 205 Placebo N = 97 Tumor grade Grade 1 / grade 2 63% / 37% 67% / 33% Metastatic extent of disease† Liver 80% 78% Lymph node or lymphatic system 42% 46% Lung 22% 21% Bone 21% 16% Median time from initial diagnosis to randomization, months (range) 29.9 (0.7-258.4) 28.9 (1.1-303.3) Median time from most recent progression until enrolment, months (range)‡ 1.68 (0.0-7.8) 1.45 (0.2-11.8) Prior treatments Somatostatin analogues 53% 56% Surgery 59% 72% Chemotherapy 26% 24% Radiotherapy including PRRT 22% 20% Locoregional and ablative therapies 11% 10% †Organs as per target and non-target lesion locations observed at baseline by central radiology review. ‡Patients were expected to have disease progression in ≤ 6 months prior to enrolment as per inclusion criteria. Protocol deviation was reported in 7 patients. Baseline and Disease Characteristics (2/2)
Primary Endpoint: PFS by Central Review 52% reduction in the relative risk of progression or death with everolimus vs placebo HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001 P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. 205 168 145 124 101 81 65 52 26 10 3 0 0 97 65 39 30 24 21 17 15 11 6 5 1 0Placebo Everolimus No.of patients still at risk 0 2 4 6 8 10 12 15 18 21 24 27 30 Months 0 10 20 30 40 50 60 70 80 90 100 ProbabilityofProgression-freeSurvival(%) Kaplan-Meier medians Everolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43) Censoring Times Everolimus (n/N = 113/205) Placebo (n/N = 65/97)
Consistent Investigator-Assessed PFS P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. Everolimus vs Placebo HR = 0.39 (95% CI, 0.28-0.54); P < 0.00001 205 171 148 132 108 93 75 59 33 15 5 0 97 70 47 35 27 25 21 19 10 6 4 0Placebo Everolimus Time (Months) 0 10 20 30 40 50 60 70 80 90 100 ProbabilityofProgression-freeSurvival(%) No.of patients still at risk Kaplan-Meier medians Everolimus: 14.0 months (95% CI, 11.24-17.71) Placebo: 5.5 months (95% CI, 3.71-7.39) Censoring Times Everolimus (n/N = 98/205) Placebo (n/N = 70/97) 2 4 6 8 10 12 15 18 21 24 270 30 0 0
Consistent PFS HR by Stratification Factors, Central Review Hazard ratio obtained from unstratified Cox model. NET, neuroendocrine tumors; SSA, somatostatin analogues; WHO PS, World Health Organization performance status. Prior SSA treatment Yes No Tumor origin* Stratum A Stratum B WHO PS 0 1 157 145 153 149 216 86 Hazard Ratio (95% CI)No.Subgroups 0.52 (0.34-0.81) 0.60 (0.39-0.94) 0.63 (0.40-1.02) 0.43 (0.28-0.66) 0.58 (0.41-0.84) 0.50 (0.28-0.91) 0.1 0.4 1 10 Everolimus Better Placebo Better *Based on prognostic level, grouped as: Stratum A (better prognosis) - appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary). Stratum B (worse prognosis) - lung, stomach, rectum, and colon except caecum).
PFS HR by Primary Liver Tumor Burden, Central Review Hazard ratio obtained from unstratified Cox model. None ≤10% >10%-25% >25% Hazard Ratio (95% CI)Liver Tumor Burden 48 180 37 35 No. 0.49 (0.20-1.20) 0.67 (0.45-1.00) 0.62 (0.20-1.93) 0.18 (0.06-0.50) 0.1 0.4 1 10 Everolimus Better Placebo Better
Interim Overall SurvivalAnalysis *P-value boundary for significance = 0.0002. P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. NS, not significant. 205 195 184 179 172 170 158 143 100 59 31 5 0 97 94 86 80 75 70 67 61 42 21 13 5 0Placebo Everolimus No. of patients still at risk 0 2 4 6 8 10 12 15 18 21 24 27 30 Months 0 10 20 30 40 50 60 70 80 90 100 ProbabilityofOverallSurvival(%) Censoring Times Everolimus (n/N = 42/205) Placebo (n/N = 28/97) Everolimus vs Placebo HR = 0.64 (95% CI, 0.40-1.05); P = 0.037 (NS)* First interim OS analysis performed with 37% of information fraction favored the everolimus arm Next interim analysis is expected in 2016
Best Overall Response and Tumor Shrinkage, Central Review 100 75 50 25 0 25 50 75 100 Best%ChangefromBaseline inSizeofTargetLesions Everolimus Placebo Increase in tumor size as best response Decrease in tumor size as best response 100 75 50 25 0 25 50 75 100 ************** ************* Best Overall Response Everolimus N = 205, n (%) Placebo N = 97, n (%) ORR (CR + PR) 4 (2.0) 1 (1.0) DCR (CR + PR + SD) 169 (82.4) 63 (64.9) PD 19 (9.3) 26 (26.8) Unknown 17 (8.3) 8 (8.2) 64% of patients receiving everolimus had any degree of tumor shrinkage vs 26% receiving placebo *Fourteen patients (7.6%) in the everolimus arm and 13 patients (15.3%) in the placebo arm showed a change in the available target lesion that contradicted the overall response. CR, complete response; DCR, disease control rate; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
AEs Consistent with Known Safety Profile of Everolimus Everolimus N = 202 Placebo N = 98 Drug-related adverse events All grades Grade 3/4 All grades Grade 3/4 Stomatitis* 63% 9% 19% 0 Diarrhea 31% 7% 16% 2% Fatigue 31% 3% 24% 1% Infections† 29% 7% 4% 0 Rash 27% 1% 8% 0 Peripheral edema 26% 2% 4% 1% Nausea 17% 1% 10% 0 Anemia 16% 4% 2% 1% Decreased appetite 16% 1% 6% 0 Asthenia 16% 1% 5% 0 Non-infectious pneumonitis‡ 16% 1% 1% 0 Dysgeusia 15% 1% 4% 0 Cough 13% 0 3% 0 Pruritus 13% 1% 4% 0 Pyrexia 11% 2% 5% 0 Dyspnea 10% 1% 4% 1% Hyperglycemia 10% 3% 2% 0 Presented are drug-related adverse events in ≥10% of patients (safety set). *Includes stomatitis, aphthous stomatitis, mouth ulceration, and tongue ulceration. †Includes all infections. ‡Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis.
Deaths (Safety Set) Everolimus N = 202 Placebo N = 98 All deaths, n (%) 41* (20.3) 28 (28.6) On-treatment deaths,† n (%) 7 (3.5) 3 (3.1) Due to Study indication, n (%) 4 (2.0) 1 (1.0) Other reasons, n (%) 3 (1.5) 2 (2.0) Cardiac failure 1 (0.5) 0 Septic shock 1 (0.5) 0 Lung infection 0 1 (1.0) Respiratory failure 1 (0.5) 0 Dyspnea‡ 0 1 (1.0) *Does not include one patient randomized to everolimus arm who was never treated and died †On-treatment deaths are deaths which occurred up to 30 days after the discontinuation of study treatment. ‡Occurred in a 75-year-old female on placebo arm, suspected to be treatment related. Death was preceded with thoracocentesis for pleural effusion related to disease progression, followed by clinical and hematological signs of infection (most probably pleurisy with septic shock).
8888 Sunitinib vs Placebo in Advanced pNET: • Phase III randomized, placebo-controlled, double-blind trial • Trial stopped after early unplanned analysis showed efficacy and safety benefit Primary Endpoint: PFS Secondary Endpoints: OS, ORR, TTR, duration of response, safety, and patient-reported outcomes Patients with advanced pNET, N = 171/340 patients enrolled Sunitinib 37.5 mg/day orally Continuous daily dosing* n = 86 Placebo* n = 85 *With best supportive care Somatostatin analogues were permitted Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. 1:1 R A N D O M I Z E
89 89 0.8 0.6 0.4 0.2 0 1.0 ProportionofPatients 5 10 15 20 250 Sunitinib 39 19 4 0 086Sunitinib 28 7 2 1 085Placebo Number at risk Time (mo) Placebo Kaplan-Meier median PFS Sunitinib: 11.4 mo Placebo: 5.5 mo HR = 0.42 (95% CI, 0.26–0.66) P<0.001 Progression-free Survival:* Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. * Local review
1.0 Objective response: Stable disease: Median survival: 34% 5% 94.6 months Open phase II study, 1,109 patients with progressive NET (within 12 months), 2,472 cycles 90Y-DOTA- TOC-therapy, median follow up 23 months • Objective response rates 30% - 40% • Survival benefit in responders likely • Limitations: safety concerns (renal, bone marrow toxicity), limited availability, lacking randomized studies 0 2 4 6 8 10 12 Time Since Start of Treatment, years 14 0.2 0.4 0.6 0.8 OverallSurvival,probability Imhof A, et al. J Clin Oncol. 2011;29(17):2416-1423. No. of patient s No. of deaths Median survival Hazard ratio P Disease control 671 280 3.8 years 0.41 vs progress <.001 Progress 438 211 1.4 years PRRT:
NEW COMERS:
Pazopanib in NET: • 52 patients with G 1 – 2 NET. • 32 patients with Pancreatic NET. • 20 patients with Carcinoid Tumors. • Pazopanib 800 mg daily + Octreotid Depot till progression or 12 months of therapy. Alexandria T Phan* et al. Lancet Oncol 2015; 16: 695–703 21.9% 0%
Pazopanib in NET: Alexandria T Phan* et al. Lancet Oncol 2015; 16: 695–703 14.4 ms 12.2 ms 25 ms 18.5 ms
NET – Treatment Algorithm:
TAKE HOME MESSAGE: • NENs are heterogeneous, and we need to deal with hormone release, tumor growth rate and related symptoms • A different staging classification to other solid tumors is used for NENs, joining TNM and grading systems • SSAs are the cornerstone of therapy for hormone- related symptoms and recently showed their antiproliferative effect in G1/Low G2 enteropancreatic NETs • Better knowledge of molecular biology has prompted the development of targeted therapies for NETs, that should be integrated with SSAs, chemotherapy, PRRT and loco- regional therapies

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Neuroendocrine Tumors in 2016

  • 1.
    NEUROENDOCRINE TUMORS: Mohamed AbdullaM.D. Prof. of Clinical Oncology Cairo University Asyut Clinical Oncology Annual Conference NOVARTIS Symposium 23/02/2016 “Capture a MACRO Portrait”
  • 2.
    Disclosures: • Amgen • MerckSerono • Janssen Cilag • Astra Zeneca • Pfizer • Astellas. • Hoffman La Roche • Novartis
  • 3.
    Challenges: • Rare • OneCell of Origin  Many Locations  Many Faces. • +/- Hormonal Syndromes. • Problems of Diagnosis. 1. Clinically VAGUE. 2. TISSUE DIAGNOSIS. • Delayed Onset of Diagnosis  Advanced Disease. • Lacking of Response to Available Treatment Options A HASSLE & WASTE OF RESOURCES OR REAL UNDERESTIMATED PROBLEM?
  • 4.
    Origin: Neuropeptides Catecholamines Hormonal Syndromes Lawrence B, GustafssonBI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40:1.
  • 5.
  • 6.
    Incidence of NETsIs Increasing* 8 8 SEER = Surveillance, Epidemiology, and End Results (for malignant NETs) *Approximate 5-fold increase between 1975 and 2004 Approximate 7-fold increase also evident in Norwegian registry IncidencePer100,000 1.40 Year NET Site 1.20 1.00 0.80 0.60 0.40 0.20 0 Lung Colon Small intestine Rectum Pancreas Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.
  • 7.
    Colon Neuroendocrine Stomach 29-yearlimited duration prevalence analyses based on SEER Pancreas Esophagus Hepatobiliary 0 100 1,100 NET Prevalence in the US, 2004 1,200 Median survival (1988 – 2004)103,312 cases (35/100,000) No.ofcases (thousands) Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. NETs Are the 2nd-Most Prevalent Gastrointestinal Tumor: • Localized • Regional • Distant 203 months 114 months 39 months
  • 8.
    NET: Demographics: Lepage C,et al. Gut. 2004;53(4):549-553.
  • 9.
    descendin g colon (<1%) sigmoid colon (- 12%) PrimaryTumor Localizations est. % of all NEN thymus bronchus esophagus stomach duodenum pancreas jejunum/ileum cecum appendix colon rectum <1 15 <1 15 4 15 15 2 15 1 10 thymus (1%) bronchus (-15%) esophagus (<1%) pancreas (-15%) duodenum (-4%) ascending colon (- 1%) jejunum (-5%) ileum (-10%) cecum (-2%) appendix (-15%) rectum (-10%) stomach (-15%) Pape UF, et al. Gastroenterol up2date. 2011;7:313- 339.
  • 10.
    Hormone Hypersecretion Syndromes (=Functioning NET) Calcitonin Somatostatinoma Cushing syndrome Atypical carcinoid syndrome Verner Morrison syndrome (VIPom) Glucagonoma Gastrinoma Insulinoma Carcinoid syndrome 0 20 40 60 80 100 120 140 160 180 200 220 240 244 158 76 16 8 5 6 2 1 Begum N, et al. Zentralbl Chir. 2014;139(3):276-283. Functioning: 39.5% (553) Non-functioning: 60.0% (836) Unclear: 0.5% (11)
  • 11.
  • 12.
    Pathogenesis of Carcinoid: TRYPTOPHANMETABOLISM NORMAL NET 1% SEROTONIN 70% SEROTONIN FOREGUT MIDGUT HINDGUT Aromatic L- Amino Acid Decarboxylase
  • 13.
    Pathogenesis of Carcinoid: MarcDíez, Alexandre Teulé, Ramon Salazar.Ann Gastroenterol 2013; 26 (1): 29-36
  • 14.
    Pathogenesis of Carcinoid: Somatostatin:The Natural Defense Mechanism: SOMATOSTATIN Somatostatin Receptors Short Lived Bio-availability
  • 15.
    Niederle MD, etal. Endocr Relat Cancer. 2010;17(4):909-918. Biologicalbehavior Malignant Uncertain Benign NET: Not all the same:
  • 16.
    Key Issues inThe Management: 1. How do we define the disease? Nomenclature, Classification & Pathology. 2. Who needs treatment and when? Patient Selection. 3. Which treatment and in what sequence? Treatments. 4. What is the role of combined biologics, somatostatin analogues, cytotoxics and biomarkers? Unanswered Questions.
  • 17.
    1.How do wedefine the disease? Nomenclature, Classification and Pathology
  • 18.
    Evolution of Terminology& Classification: Historic Evolution: 1907 1963 1970 1980 1995 Carcinoid Williams & Sandler Soga & Tazawa Histologic WHO Granular Stain Techniques Capella Size & Invasion • Benign. • Benign or Low Grade Malignant. • Low Grade Malignant. • High Grade Malignant. No Prognostic or Predictive Validation
  • 19.
  • 20.
    Evolution of Terminology& Classification: Histopathologic Differentiation: Well Differentiated Poorly Differentiated
  • 21.
    Evolution of Terminology& Classification: AJCC Criteria of Grading: Grade Mitotic Count (per 10 HPF) Ki 67 Index (%) G1 < 2 < 2 G2 2 – 20 3 – 20 G3 > 20 > 20 AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.
  • 22.
    Evolution of Terminology& Classification: Correlation of Tumor Grade With Survival: 1. Rindi G, Klöppel G, Alhman H, et al. Virchows Arch. 2006;449:395-401. 2. Rindi G, Klöppel G, Couvelard A, et al. Virchows Arch. 2007;451:757-762. 3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer. 2008;113:256-265. 0 50 100 150 200 250 Survival Time (mo) 0.0 0.2 0.4 0.6 0.8 1.0 CumulativeSurvival G1 G2 G3 G1 vs G2 G1 vs G3 G2 vs G3 P=0.040 P<0.001 P<0.001 N=193
  • 23.
    Scarpa A, etal. Mod Pathol. 2010;23(6):824- 833. < 2% 15% 75% Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097. Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798- 7803. Vilar E, et al. Endocr Relat Cancer. 2007;14(2):221- 232. Prognostic Influence of Ki67-Labelling
  • 24.
    Evolution of Terminology& Classification: Correlation of TNM Staging With Survival: 26 26 La Rosa S, Klersy C, Uccella S, et al. Hum Pathol. 2009;40:30-40. Patients With Well-Differentiated Pancreatic NET Stage I P<0.001 ProportionAlive Stage II Stage III Stage IV I (n = 44) II (n = 44) III (n = 34) IV (n = 33) Time (mo) 0.00 0.25 0.50 0.75 1.00 0 48 96 144 192 240
  • 25.
    Evolution of Terminology& Classification: NETs Are Often Diagnosed Late: Vinik AI, Silva MP, Woltering EA, et al. Pancreas. 2009;38:876-889. 1 2 3 4 5 6 7 8 9 Time (yr) Primary tumour growth Metastases Flushing Diarrhea Death Vague abdominal symptoms Estimated time to diagnosis: 5 to 7 yr * * *Symptoms of carcinoid syndrome
  • 26.
    Evolution of Terminology& Classification: Metastatic Disease Is Common at Presentation: Localized Metastatic 50% 27% 23% Distant metastases Regional spread Data from an analysis of 28,515 cases of NET identified in the SEER registries Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072. *These data are of the cases in which stage was reported. 20% of cases did not provide disease stage information
  • 27.
    Pathology Report ofNETs • Define location and tumor type based on WHO classification • Define tumor grade (including Ki-67 proliferative index) • Describe the presence of additional histologic features (multicentric disease, non-ischemic tumor necrosis, vascular or perineural invasion) • Assess the TNM stage • Define the resection margins • Define the hormonal production, if any • Upon request, assess prognostic or predictive factors useful for target therapy (eg, somatostatin receptors, mTOR pathway molecules, other target enzymes, …) Klimstra D, et al. Am J Surg Pathol. 2010;34(3):300-313.
  • 28.
    2. Role ofBiomarkers & Imaging:
  • 29.
    Pan-neuroendocrine markers Cytosolic NSE,PGP 9.5 Related to secretory granules Chromogranin Related to synaptic vesicles Synaptophysin, VMAT Intermediate filaments NF, CK HMW Adhesion molecules N-CAM Immunohistochemical NE markers:
  • 30.
     Chromogranin A* (in70%-90% increased in metast. NET)  Pancreatic Polypeptide, PP (in 40%-55 % elevated);  a-HCG, β-HCG (in ~ 30% elevated)  Neuron specific enolase (NSE) (in ~33% elevated) *The height of Chromogranin A level correlates with tumor load, an increase over time indicates tumor progression Circulating Tumor Markers:
  • 31.
    CgA correlates withhepatic tumor load Heigher CgA levels indicate lower survival Arnold R, et al. Clin Gastroenterol Hepatol. 2008;6(7):820-827 Prognostic Value of CgA:
  • 32.
    HR = 0.25 95%CI: 0.13-0.51 P = .00004 Median PFS Early response = 13.3 mos. No early response = 7.5 mos. 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 HR = 0.25 95% CI: 0.10-0.58 P = .00062 CgA NSE Median PFS Early response = 8.6 mos. No early response = 2.9 mos. PFS(%) 0 20 40 60 80 100 0 20 40 60 80 100 Time Since Study Start, months Time Since Study Start, months Pts at Risk Pts at Risk Resp. 33 29 26 19 12 5 3 2 0 Resp. 28 23 16 9 6 3 1 0 0 Nonresp 38 26 12 5 1 1 0 0 0 Nonresp. 11 5 2 0 0 0 0 0 0 Yao JC, et al. J Clin Oncol. 2010;28(1):69-76. RADIANT-1 (Stratum I) Predictive Value of Biomarkers: PFS by Early CgA and NSE Responses:
  • 33.
    Modlin IM, etal. Ann Surg Oncol. 2010;17(9):2427-2443. PPI Chronic Atrophic Gastritis PPI H2RAs Small cell lung cancer Prostate cancer Breast cancer Ovary Cancer Chronic atrophic gastritis Pancreatitis Inflammatory bowel disease Irritable bowel syndrome Liver cirrhosis Chronic hepatitis Colon cancer HCC Pancreatic adenocarcinoma Pheochromocytoma Hyperparathyroidism Pituituary tumors Medullary thyroid carcinoma Hyperthyroidism CgA ENDOCRINE DISEASE GASTRO- INTESTINAL DISORDERS NON-GI CANCER Arterial hypertension Cardiac insufficiency Acute coronary syndrome Giant cell arteritis CARDIOVASCULAR DISEASE Systemic rheumatoid arthritis Systemic inflammatory response syndrome Chronic bronchitis Airway obstruction in smokers INFLAMMATORY DISEASES Renal Insufficiency RENAL DISORDERS DRUGS Causes of Chromogranin A Elevation:
  • 34.
    Diagnosis: Imaging PrimaryTumor/Tumor Spread:  Whole body Screening & Staging  Endocrine Pancreatic tumor < 1cm  Routine imaging  Primary tumour Screening & Staging (optional)  Octreoscan (111Indium-DTPA- Octreotide)/ SPECT: 1. choice  Endoscopic ultrasonography  ultrasonography of the liver  CT (+ angiography), MRI  Positron emission tomography (PET) with 11C-5 HTP,11C-L-dopa or 18F-FDG  SMS-R-PET: 68Gallium-DOTATOC- PET  PET/CT ENETS-Guidelines 2011
  • 35.
    3. Therapy forAdvanced Disease “Symptom Control & Cytotoxic Therapy”
  • 36.
    Therapy of NETs Threeprinciples • Control of hormonal symptoms • Control of tumor growth • Improvement of survival? Symptomatic therapy Surgical therapy Antiproliferative therapy • Cure • Debulking • Treatment / Prevention of complications
  • 37.
    Resection of primarytumor in distant metastatic disease? 249 primary resected, MS = 7.4 y Hellman et al, 2002 Givi et al, 2006 Ahmed et al, 2009 Rinke et al 2009 Resection of primary tumor (intestine) and impact on prognosis
  • 38.
    Survival after resectionof liver metastases Consenus Conference, London 2012 Frilling et al, 2014, *Sarmiento et al 2003, Elias et al 2003, Glazer et al 2010, Mayo et al 2010 Limitations Complete resection in 20–57% Recurrence in up to 94% after 5 years* No randomized trials
  • 39.
    Therapy of GEP-NETs:Shifting From Symptom Management to Targeting Tumors Somatostatin analogues Symptomatic therapy (carcinoid syndrome) Control of tumor growth
  • 40.
    Possible Mechanisms forAntiproliferative Activities of SSAs Antiproliferative effect of SSA Direct antiproliferative effect Indirect antiproliferative effect Binding to the somatostatin receptor on tumor cells Systemic effect Inhibition of cell cycle Inhibition of growth factor effects Pro- apoptotic effect Inhibition of growth factor and trophic hormones Inhibition of angiogenesis Immune system modulation Susini C, et al. Ann Oncol. 2006;17(12):1733-1742.
  • 41.
    Somatostatin Receptors (SSTR)Are Expressed by the Majority of NETs • SSTR2 is most prevalent in GEP-NETs and induces inhibitory effects on hormone secretion and proliferation in NETs • Somatostatin is effective in controlling NET-related hormonal symptoms • Clinical use of somatostatin is limited by its short half life Basu B, et al. Endocr Relat Cancer. 2010;17(1):R75-R90. Modlin IM, et al. Aliment Pharmacol Ther. 2010;31(2):169-188. Hofland LJ. J Endocrinol Invest. 2003;26(8 Suppl):8-13. Ferrante E, et al. Endocr Relat Cancer. 2006;13(3):955-962. Prevalence on NET type: SSTR1 SSTR 2 SSTR3 SSTR4 SSTR5 Pancreas 68% 95% 46% 93% 57% Midgut 80% 86% 65% 35% 75% Inhibitory effect: Hormone secretion + + + Proliferation + + + + Induction of apoptosis + +
  • 42.
    • Octreotide andlanreotide show high affinity for the SSTR2 and are approved for antisecretory treatment in NETs LAR, long lasting release Susini C, et al. Ann Oncol. 2006;17(12):1733- 1742. Octreotide LAR (10-30 mg / 28 days im) Lanreotide (60-120 mg / 28 days sc) Octreotide (2-3 x 50-500 ug sc / d) Biotherapy of Functional Active NETs With Somatostatin Analogs (SSA) S S a l a g l y ly asn s cys p h e p h e p h e tr p l y s t h r p h e t h r s e r cys D-phe c y s phe l y s c th y r s Octreotide acetate D-trp Thr - ol D-phe c l y s v al c y y s S ty r s Lanreotid e D-trp Thr - NH2 S Somatostatin S S
  • 43.
    Phase III Studyof Octreotide LAR: PROMID Study: Patients: • Well-differentiated midgut NET • Treatment-naïve • Locally inoperable or metastasized N = 85 Octreotide LAR 30 mg im/28 days Placebo im/28 days Primary endpoint: • Median time to tumour progression Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663. 1:1 R A N D O M I Z E Secondary endpoints: •Objective tumour response rate • Symptom control • Overall survival Treatment until CT/MRI documented tumour progression or death Randomized, Double-blind, Placebo-controlled Study
  • 44.
    Octreotide LAR 30mg Significantly Prolongs TTP: HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumours; TTP = time to progression Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663. Octreotide LAR vs placebo HR=0.34 P=0.000072 [95% CI: 0.20–0.59] Based on conservative ITT analysis ProportionWithout Progression 1.0 .75 .50 .25 0 0 6 12 18 24 30 36 42 Time (mo) 48 54 60 66 72 78 Octreotide LAR (n = 42) Median 14.3 mo Placebo (n = 43) Median 6.0 mo
  • 45.
    Octreotide LAR 30mg Extends TTP in Patients With Functioning and Nonfunctioning Tumours: 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Based on the per-protocol analysis P=0.0008; HR=0.25 (95% CI: 0.10–0.59) ProportionWithoutProgression P=0.0007; HR=0.23 (95% CI: 0.09–0.57) ProportionWithoutProgression Patients with nonfunctioning tumours Patients with functioning tumours Time (mo)Time (mo) Octreotide LAR 30 mg: 17 pts/11 events Median TTP 14.26 mo Placebo: 16 pts/14 events Median TTP 5.45 mo Octreotide LAR 30 mg: 25 pts/9 events Median TTP 28.8 mo Placebo: 27 pts/24 events Median TTP 5.91 mo 1. Arnold R, Müller H, Schade-Brittinger C, et al. J Clin Oncol. 2009;27(suppl):15s. Abstr 4508. 2. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
  • 46.
    Octreotide LAR (n=42) Placebo (n=43) Complete response(n) 0 0 Partial response (n) 1 1 Stable disease (n) 28 16 Progressive disease (n) 10 23 Unknown (n) 3 3 Wilcoxon-Mann-Whitney: P=0.0079 Octreotide LAR Achieved Superior Tumor Response at 6 Months (WHO): Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
  • 47.
    The PROMID Study:Octreotide LAR in Midgut NETs – What Did We Learn? Lessons Limitations Rinke A, et al. J Clin Oncol. 2009;27(28): 4656-4663. Octreotide LAR shows antitumor effect in: • Midgut tumors • Low hepatic tumor burden (<10%) • Grade 1 tumors The efficacy of SSAs is uncertain in: • Non-midgut tumors • Higher liver tumor burden (<10%) • Grade 2 tumors • Progressive disease Would an antiproliferative effect be replicable, with lanreotide, in a larger and more advanced population with GEP-NETs?
  • 48.
    Lanreotide Acetate inNET: • Patient Characteristics: Clarinet Trial: • Well to Moderately differentiated. • Ki 67 < 10% • Pancreas, mid-gut, hind-gut, or Unknown origin. N Engl J Med 2014;371:224-33.
  • 49.
    The SYM-NET StudyDESIGNASSESSMENTS Anon-interventional cross sectional study to assess SYMptom control in neuroendocrine tumors (NET) Non-interventional, cross-sectional study 273 patients suffering from NET, already treated with lanreotide for at least 3 months and with history of diarrhea due to carcinoid syndrome were enrolled Subject questionnaires Investigator review of medical record Likert scales • Patient satisfaction • Symptom severity • Perception change diarrhea • Feelings about conse- quences on daily life QoL • EORTC C30 • EORTC GI- NET21 Demography Medical history Treatment with lanreotide Diarrhea Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ characteristics • At Tt initiation • Day of visit Other clinical data • At Tt initiation • Day of visit Qol = quality of life
  • 50.
    SYM-NET Study –Results and Conclusion Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ • An improvement was observed for the majority of patients in all symptoms – 76 % patient satisfaction with diarrhea control (primary objective) – 73 % patient satisfaction with flushing control – QoL questionnaires showed a high level of activity capacity and low symptoms score • Patient-reported "subjective" information was consistent with investigator’s observation • Confirms in real life setting the satisfactory effect of lanreotide on symptoms of hormonal excess in GEP- NETs
  • 51.
    Symptom relief incarcinoid syndrome by Somatostatin analogsSymptomaticresponse(%) 0 25 50 75 100 Octreotide Octreotide LAR Lanreotide Lanreotide slow release / autogel Mean: 74.2 Median: 71 Mean: 77.3 Median: 75 mean: 63.0 median: 63 mean: 67.5 median: 63 Modlin IM, et al. Alimentary Pharmacol Ther. 2010;31:169-88. Studies (n) 11 7 1 7 Patients (n) 261 122 30 185
  • 52.
    Objective response rate:<20 % n = 367 STZ, streptozotocin; 5FU, 5-flurouracil; DOX, doxorubicin Moertel CG, et al. Cancer Clin Trials. 1979;2(4):327-334. Engstrom PF, et al. J Clin Oncol. 1984;2(11):1255-1259. Bukowski RM, et al. Cancer. 1987;60(12):2891-2895. Sun W, et al. J Clin Oncol. 2005;23(22):4897-4904. Öberg K, et al. Ann Oncol. 2010;21:v223–v227. Chemotherapy Is Not Effective in NETs Grade 1/ Grade 2 of the Midgut (Carcinoids) Reference Type of tumor Regimen No. of patients Objective response Response duration (months) Median survival (months ) Moertel and Carcinoids 5FU + cyclophosphamide 47 33 – – Hanley STZ + 5FU 42 33 – – Engstrom et al Carcinoids STZ + 5FU 80 22 8 16 DOX 81 21 6.5 12 Bukowski et al Carcinoids STZ + DOX + 5FU + cyclophosphamide STZ + 5FU + 56 9 31 22 – – – 10.8 cyclophosphamide Sun et al Carcinoids DOX + 5FU 25 15.9 4.5 15.7 STZ + 5FU 27 16 5.3 24.3
  • 53.
    Chemotherapy for G3NET: NORDIC Trial: Annals of Oncology 24: 152–160, 2013
  • 54.
    Temozolomide in Pancreatic NeuroendocrineCarcinoma Strosberg JR, et al. Cancer 2011;117(2):268-275 Capecitabine Temozolomide every 28 days 750 mg/m2 x 2 x tgl. (days 1– 14) 200 mg/m2 x 1 (days 10–14); n = 30: 22 NF; 2 gastrinoma; 2 insulinoma; 2 VIPoma; 1 glucagonoma; 1 gastrinoma/glucagonoma 70% PR (RECIST ) Median PFS: 18 months Retrospective analysis G3–4 adverse events (12%): anemia, thrombocytopenia, elevation of liver enzymes 100 80 60 40 20 0 –20 –40 –60 –80 –100 Progressive Disease Partial Response
  • 55.
  • 56.
    Streptozocin/5-Fu are RE-EMPOWERED in2015: RR & Treatment Outcome:
  • 57.
    Streptozocin/5-Fu are RE-EMPOWERED in2015: Which Subset Got Benefit?
  • 58.
    4. Molecular Events&Targeted Therapies.
  • 60.
    Molecular Events &Therapeutic Implications: 1. Angiogenesis: vHL Gene OxygenationHypoxia +++ VEGFAngiogenesis PFS 96% 68% Bevacizumab + Octreotid LAR INF + Octreotid LAR Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, Hess K, Ng C, Abbruzzese JL, Ajani JA. J Clin Oncol. 2008;26(8):1316.
  • 61.
    Molecular Events &Therapeutic Implications: 2. mTOR Pathway: Mammalian Target of Rapamycin mTORC1 mTORC2 Protein Synthesis Cell Growth Autophagy Altered Metabolism Increased Proliferation Apoptosis Resistance +++ +++ RTK AKT PI3K RAS –RAF MEK
  • 62.
    Targeted Drugs in NeuroendocrineTumors  Novel Somatostatin analogues: Pasireotide (SOM230), chimeric molecules (e.g. Dopastatin)  Others: Tryptophan hydroxylase inhibitor (Telotristat Etiprate, LX1606), IGF-1 R antagonists/ antibodies, HDAC inhibitors etc  Angiogenesis inhibitors: VEGF-Receptor-Tyrosinkinase-Inhibitor PTK787/ZK, Anti-VEGF (Bevacizumab), Endostatin, Thalidomide  Single / multiple tyrosine kinase inhibitors: Imatinib, Gefitinib, Sorafenib, Sunitinib  mTOR Inhibitors: Temsirolimus, Everolimus
  • 63.
    Everolimus 10 mg/d+ best supportive care1 n = 207 RADIANT-3: Study Design Placebo + best supportive care1 n = 203 Multiphasic CT or MRI performed every 12 weeks Treatment until disease progression Patients with advanced pNET, N = 410 Stratified by: • WHO PS • Prior chemotherapy Crossover 1:1 R A N D O M I S E Phase III, Double-Blind, Placebo-Controlled Trial Primary Endpoint: PFS Secondary Endpoints: OS, ORR, biomarkers, safety, pharmacokinetics (PK) Yao J, Shah M, Ito T, et al. N Engl J Med. 2011;364:514-523. 1:1
  • 64.
    RADIANT-3: Baseline Characteristics Everolimus(n = 207) Placebo (n = 203) Median age, years (range) 58 (23-87) 57 (20-82) Male : Female (%) 53 : 47 58 : 42 WHO PS (%) 0 / 1 / 2 67 / 30 / 3 66 / 32 / 3 No. of disease sites(%) 1 25 31 2 41 32 ≥3 34 38 Histologic Grade (%) Well differentiated 82 84 Moderately differentiated 17 15 Unknown 1 1 Prior Treatment (%) Somtatostatin analogues 49 50 Chemotherapy 50 50 Radiotherapy 23 20 Yao J, Shah M, Ito T, et al. N Engl J Med. 2011;364:514-523.
  • 65.
    RADIANT-3 PFS by InvestigatorReview: • P value obtained from stratified 1-sided log-rank test • Hazard ratio is obtained from stratified unadjusted Cox model %Event-free 0 2 4 6 8 10 No. of patients still at risk Kaplan-Meier median PFS Everolimus: Placebo: 11.0 mo 4.6 mo Hazard ratio = 0.35; 95% CI 0.27–0.45 P value: <.0001 PFS rate (18 mos.) Everolimus 34.2% Placebo 8.9% Yao JC, et al. N Engl J Med. 2011;364(6):514- 523. 12 14 16 18 Time (mo) 100 80 Censoring times Everolimus (n/N = 109/207) Placebo (n/N = 165/203) 60 40 20 0 20 22 24 26 28 30
  • 66.
    • Everolimus toxicitieswere similar to those seen in other tumour types • Most frequently reported all-grade treatment-related AEs with everolimus were stomatitis (64%), rash (49%), diarrhea (34%), fatigue (31%), and infections (23%) • Grade 3/4 AEs (≥5%) in the everolimus arm included stomatitis (7%), anemia (6%), and hyperglycemia (5%) Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523. RADIANT-3: Treatment-Related Adverse Events
  • 67.
    RADIANT-3: Summary • Everolimustherapy resulted in a statistically and clinically significant 6.4-month increase in median PFS (4.6 months to 11.0 months) • Everolimus provided a 65% reduction in risk for progression compared to placebo (HR = 0.35, P<.0001) • PFS rate at 18 months: 34% everolimus versus 9% placebo demonstrates that everolimus provides a durable benefit • Everolimus has an acceptable safety profile in patients with advanced pNET
  • 68.
    RADIANT-2 Study Design: Everolimus10 mg/day + Octreotide LAR 30 mg/28 days n = 216 Placebo + Octreotide LAR 30 mg/28 days n = 213 Treatment until disease progression R A N D O M I Z E 1:1 Multiphasic CT or MRI performed every 12 wk Crossover Primary endpoint: • PFS (RECIST) Secondary endpoints: • Tumour response, OS, biomarkers, safety, PK Enrollment January 2007–May 2008 Phase III, Double-blind, Placebo-controlled Trial Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8. Patients with advanced NET (N=429) • Advanced low- or intermediate- grade NET • Radiologic progression <12 months • History of secretory symptoms (flushing, diarrhea) • Prior antitumour therapy allowed • WHO PS ≤2
  • 69.
    PFS by CentralReview:* Time (mo) No. of patients still at risk E + O P + O 216 213 202 202 167 155 129 117 120 106 102 84 81 72 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 1-sided log-rank test • HR is obtained from unadjusted Cox model E + O = everolimus + octreotide LAR P + O = placebo + octreotide LAR 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 PercentageEvent-free Kaplan-Meier median PFS Everolimus + octreotide LAR: 16.4 mo Placebo + octreotide LAR: 11.3 mo HR = 0.77; 95% CI (0.59–1.00) P=0.026 Total events = 223 Censoring times E + O (n/N = 103/216) P + O (n/N = 120/213) Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
  • 70.
    Subgroup PFS Analysis: *Independentadjudicated central review HR = everolimus + octreotide/placebo + octreotide Unstratified Cox model was used to obtain HR E + O = everolimus + octreotide LAR P + O = placebo + octreotide LAR Subgroups (N) Central review *(429) Local investigator review (429) Age group <65 yr (286) ≥65 yr (143) Gender Male (221) Female (208) WHO Performance Status WHO = 0 (251) WHO > 0 (176) Tumour histology grade Well-diff. (341) Moderately diff. (68) Primary tumour site Small intestine (224) Lung (44) Colon (28) Other (132) Prior long-acting SSA Yes (339) No (90) Prior chemotherapy Yes (130) No (299) HR Median PFS (mo) E + O P + O 0.77 16.4 11.3 0.78 12.0 8.6 0.78 19.2 13.0 0.75 13.9 11.0 0.85 13.7 13.0 0.73 17.1 11.1 0.67 21.8 13.9 0.81 13.6 8.3 0.74 18.3 13.0 0.82 13.7 7.5 0.77 18.6 14.0 0.72 13.6 5.6 0.39 29.9 13.0 0.77 14.2 11.0 0.81 14.3 11.1 0.63 25.2 13.6 0.70 13.9 8.7 0.78 19.2 12.0 Hazard Ratio Favors E + O Favors P + O 0 10.4 0.8 1.4 Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
  • 71.
  • 72.
  • 73.
  • 74.
    Everolimus: Real WorldTrial: • Med PFS = 12 months • Med OAS = 32 months • Pancreatic = Non Pancreatic
  • 75.
    RADIANT-4 Study Design *Basedon prognostic level, grouped as: Stratum A (better prognosis)  appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worse prognosis)  lung, stomach, rectum, and colon except caecum. Crossover to open label everolimus after progression in the placebo arm was not allowed prior to the primary analysis. Endpoints: • Primary: PFS (central) • Key Secondary: OS • Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK Patients with well- differentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N = 302) • Absence of active or any history of carcinoid syndrome • Pathologically confirmed advanced disease • Enrolled within 6 months from radiologic progression Everolimus 10 mg/day N = 205 Treated until PD, intolerable AE, or consent withdrawal 2:1 R A N D O M I Z E Placebo N = 97 Stratified by: • Prior SSA treatment (yes vs. no) • Tumor origin (stratum A vs. B)* • WHO PS (0 vs. 1)
  • 76.
    Characteristic Everolimus N = 205 Placebo N= 97 Age, median (range) 65 (22 – 86) 60 (24 – 83) Male / female 43% / 57% 55% / 45% WHO performance status 0 / 1 73% / 27% 75% / 25% Race Caucasian 79% 70% Asian 16% 19% Other* 5% 11% Primary tumor site Lung 31% 28% Ileum 23% 25% Rectum 12% 16% Jejunum 8% 6% Stomach 3% 4% Duodenum 4% 2% Colon 2% 3% NET of unknown primary 11% 13% Baseline and Disease Characteristics (1/2) *Included Black.
  • 77.
    Characteristic Everolimus N = 205 Placebo N= 97 Tumor grade Grade 1 / grade 2 63% / 37% 67% / 33% Metastatic extent of disease† Liver 80% 78% Lymph node or lymphatic system 42% 46% Lung 22% 21% Bone 21% 16% Median time from initial diagnosis to randomization, months (range) 29.9 (0.7-258.4) 28.9 (1.1-303.3) Median time from most recent progression until enrolment, months (range)‡ 1.68 (0.0-7.8) 1.45 (0.2-11.8) Prior treatments Somatostatin analogues 53% 56% Surgery 59% 72% Chemotherapy 26% 24% Radiotherapy including PRRT 22% 20% Locoregional and ablative therapies 11% 10% †Organs as per target and non-target lesion locations observed at baseline by central radiology review. ‡Patients were expected to have disease progression in ≤ 6 months prior to enrolment as per inclusion criteria. Protocol deviation was reported in 7 patients. Baseline and Disease Characteristics (2/2)
  • 78.
    Primary Endpoint: PFSby Central Review 52% reduction in the relative risk of progression or death with everolimus vs placebo HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001 P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. 205 168 145 124 101 81 65 52 26 10 3 0 0 97 65 39 30 24 21 17 15 11 6 5 1 0Placebo Everolimus No.of patients still at risk 0 2 4 6 8 10 12 15 18 21 24 27 30 Months 0 10 20 30 40 50 60 70 80 90 100 ProbabilityofProgression-freeSurvival(%) Kaplan-Meier medians Everolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43) Censoring Times Everolimus (n/N = 113/205) Placebo (n/N = 65/97)
  • 79.
    Consistent Investigator-Assessed PFS P-valueis obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. Everolimus vs Placebo HR = 0.39 (95% CI, 0.28-0.54); P < 0.00001 205 171 148 132 108 93 75 59 33 15 5 0 97 70 47 35 27 25 21 19 10 6 4 0Placebo Everolimus Time (Months) 0 10 20 30 40 50 60 70 80 90 100 ProbabilityofProgression-freeSurvival(%) No.of patients still at risk Kaplan-Meier medians Everolimus: 14.0 months (95% CI, 11.24-17.71) Placebo: 5.5 months (95% CI, 3.71-7.39) Censoring Times Everolimus (n/N = 98/205) Placebo (n/N = 70/97) 2 4 6 8 10 12 15 18 21 24 270 30 0 0
  • 80.
    Consistent PFS HRby Stratification Factors, Central Review Hazard ratio obtained from unstratified Cox model. NET, neuroendocrine tumors; SSA, somatostatin analogues; WHO PS, World Health Organization performance status. Prior SSA treatment Yes No Tumor origin* Stratum A Stratum B WHO PS 0 1 157 145 153 149 216 86 Hazard Ratio (95% CI)No.Subgroups 0.52 (0.34-0.81) 0.60 (0.39-0.94) 0.63 (0.40-1.02) 0.43 (0.28-0.66) 0.58 (0.41-0.84) 0.50 (0.28-0.91) 0.1 0.4 1 10 Everolimus Better Placebo Better *Based on prognostic level, grouped as: Stratum A (better prognosis) - appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary). Stratum B (worse prognosis) - lung, stomach, rectum, and colon except caecum).
  • 81.
    PFS HR byPrimary Liver Tumor Burden, Central Review Hazard ratio obtained from unstratified Cox model. None ≤10% >10%-25% >25% Hazard Ratio (95% CI)Liver Tumor Burden 48 180 37 35 No. 0.49 (0.20-1.20) 0.67 (0.45-1.00) 0.62 (0.20-1.93) 0.18 (0.06-0.50) 0.1 0.4 1 10 Everolimus Better Placebo Better
  • 82.
    Interim Overall SurvivalAnalysis *P-valueboundary for significance = 0.0002. P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. NS, not significant. 205 195 184 179 172 170 158 143 100 59 31 5 0 97 94 86 80 75 70 67 61 42 21 13 5 0Placebo Everolimus No. of patients still at risk 0 2 4 6 8 10 12 15 18 21 24 27 30 Months 0 10 20 30 40 50 60 70 80 90 100 ProbabilityofOverallSurvival(%) Censoring Times Everolimus (n/N = 42/205) Placebo (n/N = 28/97) Everolimus vs Placebo HR = 0.64 (95% CI, 0.40-1.05); P = 0.037 (NS)* First interim OS analysis performed with 37% of information fraction favored the everolimus arm Next interim analysis is expected in 2016
  • 83.
    Best Overall Responseand Tumor Shrinkage, Central Review 100 75 50 25 0 25 50 75 100 Best%ChangefromBaseline inSizeofTargetLesions Everolimus Placebo Increase in tumor size as best response Decrease in tumor size as best response 100 75 50 25 0 25 50 75 100 ************** ************* Best Overall Response Everolimus N = 205, n (%) Placebo N = 97, n (%) ORR (CR + PR) 4 (2.0) 1 (1.0) DCR (CR + PR + SD) 169 (82.4) 63 (64.9) PD 19 (9.3) 26 (26.8) Unknown 17 (8.3) 8 (8.2) 64% of patients receiving everolimus had any degree of tumor shrinkage vs 26% receiving placebo *Fourteen patients (7.6%) in the everolimus arm and 13 patients (15.3%) in the placebo arm showed a change in the available target lesion that contradicted the overall response. CR, complete response; DCR, disease control rate; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
  • 84.
    AEs Consistent withKnown Safety Profile of Everolimus Everolimus N = 202 Placebo N = 98 Drug-related adverse events All grades Grade 3/4 All grades Grade 3/4 Stomatitis* 63% 9% 19% 0 Diarrhea 31% 7% 16% 2% Fatigue 31% 3% 24% 1% Infections† 29% 7% 4% 0 Rash 27% 1% 8% 0 Peripheral edema 26% 2% 4% 1% Nausea 17% 1% 10% 0 Anemia 16% 4% 2% 1% Decreased appetite 16% 1% 6% 0 Asthenia 16% 1% 5% 0 Non-infectious pneumonitis‡ 16% 1% 1% 0 Dysgeusia 15% 1% 4% 0 Cough 13% 0 3% 0 Pruritus 13% 1% 4% 0 Pyrexia 11% 2% 5% 0 Dyspnea 10% 1% 4% 1% Hyperglycemia 10% 3% 2% 0 Presented are drug-related adverse events in ≥10% of patients (safety set). *Includes stomatitis, aphthous stomatitis, mouth ulceration, and tongue ulceration. †Includes all infections. ‡Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis.
  • 85.
    Deaths (Safety Set) Everolimus N= 202 Placebo N = 98 All deaths, n (%) 41* (20.3) 28 (28.6) On-treatment deaths,† n (%) 7 (3.5) 3 (3.1) Due to Study indication, n (%) 4 (2.0) 1 (1.0) Other reasons, n (%) 3 (1.5) 2 (2.0) Cardiac failure 1 (0.5) 0 Septic shock 1 (0.5) 0 Lung infection 0 1 (1.0) Respiratory failure 1 (0.5) 0 Dyspnea‡ 0 1 (1.0) *Does not include one patient randomized to everolimus arm who was never treated and died †On-treatment deaths are deaths which occurred up to 30 days after the discontinuation of study treatment. ‡Occurred in a 75-year-old female on placebo arm, suspected to be treatment related. Death was preceded with thoracocentesis for pleural effusion related to disease progression, followed by clinical and hematological signs of infection (most probably pleurisy with septic shock).
  • 86.
    8888 Sunitinib vs Placeboin Advanced pNET: • Phase III randomized, placebo-controlled, double-blind trial • Trial stopped after early unplanned analysis showed efficacy and safety benefit Primary Endpoint: PFS Secondary Endpoints: OS, ORR, TTR, duration of response, safety, and patient-reported outcomes Patients with advanced pNET, N = 171/340 patients enrolled Sunitinib 37.5 mg/day orally Continuous daily dosing* n = 86 Placebo* n = 85 *With best supportive care Somatostatin analogues were permitted Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. 1:1 R A N D O M I Z E
  • 87.
    89 89 0.8 0.6 0.4 0.2 0 1.0 ProportionofPatients 5 1015 20 250 Sunitinib 39 19 4 0 086Sunitinib 28 7 2 1 085Placebo Number at risk Time (mo) Placebo Kaplan-Meier median PFS Sunitinib: 11.4 mo Placebo: 5.5 mo HR = 0.42 (95% CI, 0.26–0.66) P<0.001 Progression-free Survival:* Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. * Local review
  • 88.
    1.0 Objective response: Stable disease: Median survival: 34% 5% 94.6 months Openphase II study, 1,109 patients with progressive NET (within 12 months), 2,472 cycles 90Y-DOTA- TOC-therapy, median follow up 23 months • Objective response rates 30% - 40% • Survival benefit in responders likely • Limitations: safety concerns (renal, bone marrow toxicity), limited availability, lacking randomized studies 0 2 4 6 8 10 12 Time Since Start of Treatment, years 14 0.2 0.4 0.6 0.8 OverallSurvival,probability Imhof A, et al. J Clin Oncol. 2011;29(17):2416-1423. No. of patient s No. of deaths Median survival Hazard ratio P Disease control 671 280 3.8 years 0.41 vs progress <.001 Progress 438 211 1.4 years PRRT:
  • 89.
  • 90.
    Pazopanib in NET: •52 patients with G 1 – 2 NET. • 32 patients with Pancreatic NET. • 20 patients with Carcinoid Tumors. • Pazopanib 800 mg daily + Octreotid Depot till progression or 12 months of therapy. Alexandria T Phan* et al. Lancet Oncol 2015; 16: 695–703 21.9% 0%
  • 91.
    Pazopanib in NET: AlexandriaT Phan* et al. Lancet Oncol 2015; 16: 695–703 14.4 ms 12.2 ms 25 ms 18.5 ms
  • 92.
  • 93.
    TAKE HOME MESSAGE: •NENs are heterogeneous, and we need to deal with hormone release, tumor growth rate and related symptoms • A different staging classification to other solid tumors is used for NENs, joining TNM and grading systems • SSAs are the cornerstone of therapy for hormone- related symptoms and recently showed their antiproliferative effect in G1/Low G2 enteropancreatic NETs • Better knowledge of molecular biology has prompted the development of targeted therapies for NETs, that should be integrated with SSAs, chemotherapy, PRRT and loco- regional therapies