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7 capdevila

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7 capdevila

  1. 1. Experts, acollidors i solidaris Neuroendocrine Tumors History: A not so rare disease Jaume Capdevila, MD Gastrointestinal Cancer & New Drug Development Units Vall d’Hebron University Hospital Barcelona - Spain
  2. 2. <ul><li>Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body 1 </li></ul><ul><li>NETs can be functional or nonfunctional and include a heterogeneous group of neoplasms 2,3 </li></ul><ul><ul><li>Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 3 </li></ul></ul><ul><ul><li>Islet cell tumors 2 </li></ul></ul><ul><ul><li>Typical/atypical/poorly differentiated lung carcinoid 2 </li></ul></ul><ul><ul><li>Small cell carcinoma of the lung 2,3 </li></ul></ul><ul><ul><li>Pheochromocytoma/paraganglioma 2,3 </li></ul></ul><ul><ul><li>Medullary thyroid carcinoma </li></ul></ul><ul><ul><li>Merkel cell carcinoma 2,3 </li></ul></ul><ul><ul><li>Kidney, bladder, breast, prostate, thymus… </li></ul></ul>1. Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Lancet . 1998;352(9130):799-805. 2. National Comprehensive Cancer Network. Neuroendocrine tumors. In: NCCN Practice Guidelines in Oncology: Neuroendocrine Tumors . V.1. 2008. 3. Modlin IM, Kidd M, Latich I , Zikusoka MN, Shapiro MD. Gastroenterology . 2005;128(6):1717-1751. 4 Neuroendocrine Tumors (NETs): A Diverse Group of Malignancies, a Clinical Challenge
  3. 3. <ul><li>US SEER data show a 5-fold increase in the past 30 years </li></ul>NET Incidence Is Increasing Dramatically SEER = Surveillance, Epidemiology and End Results. Adapted with permission from Yao JC, Hassan M, Phan A, et al. J Clin Oncol . 2008;26(18):3063-3072. Incidence per 100,000 1.40 1.20 1.00 0.80 0.60 0.40 0.20 0 1973 Year Lung Appendix Stomach Colon Small intestine Rectum Caecum Pancreas 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 NET Site
  4. 4. GEP-NETs Are the Most Prevalent NETs Modlin IM, Lye KD, Kidd M. Cancer . 2003;97(4):934-959.
  5. 5. WHO Classification Groups NETs by Diagnostic Factors 1. Strosberg JR, Nasir A, Hodul P, Kvols L. Gastrointest Cancer Res . 2008;2(3):113-125. 2. Klöppel G, Perren A, Heitz PU. Ann NY Acad Sci . 2004;1014:13-27.
  6. 6. Constellation of Symptoms Can Make a Differential Diagnosis Difficult Menopause Irritable Bowel Syndrome Functional Bowel Disease Anxiety Neurosis Food Allergy Asthma Alcoholism Thyrotoxicosis Peptic Ulcer NET Symptoms • Sweating • Flushing • Diarrhea • Intermittent abdominal pain • Bronchoconstriction • GI bleeding • Cardiac disease 1. Vinik A, Moattari AR. Dig Dis Sci . 1989;34(3)(suppl):14S-27S. 2. Toth-Fejel S, Pommier RF. Am J Surg . 2004;187(5):575-579. 3. Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. J Natl Cancer Inst . 2008;100(18):1282-1289. Nonspecific Symptoms Are Common to Multiple Diagnoses Estimated time to diagnosis: 5 to 7 years 3
  7. 7. NETs Are Often Advanced at the Time of Diagnosis <ul><ul><li> M 1 at Dx: SV 5 and M 1 : </li></ul></ul><ul><ul><li>Carcinoids </li></ul></ul><ul><ul><ul><li>Small intestine 70% 55 % </li></ul></ul></ul><ul><ul><ul><li>Colon 71% 20 % </li></ul></ul></ul><ul><ul><ul><li>Appendix 10% 34 % </li></ul></ul></ul><ul><ul><ul><li>Rectum 15% 30 % </li></ul></ul></ul><ul><ul><li>Pancreatic NETs 76% 34 % </li></ul></ul>1. Yao JC, Hassan M, Phan A, et al. J Clin Oncol . 2008;26(18):3063-3072. 2. Soga J. Cancer. 2005;103(8):1587-1595. 3. Alexiev BA, Drachenberg CB, Papadimitriou JC. Diagn Pathol . 2007;2:28. 4. Modlin et al. Cancer 2003, 97:934 Local Regional Metastatic Poorly differentiated metastatic Median survival (years) 1 Well and moderately differentiated 18.5 9.25 2.75 0.4
  8. 8. Advanced disease treatment: current status Debulking surgery in M1 - SV 5 years >60% (>80% if R0) - Without surgery: 30-50% - Liver transplantation discussed 1. Norton JA et al. Surgery 2003 2. Ruszniewski et al. Digestion 2000 3. Vilar et al., Endocrine Rel Cancer 2007 4. Modlin, et al. Lancet Oncol 2008. 5. Kwekkeboom DJ, et al. JCO 2008 SURGICAL TREATMENT CHEMOEMBOLITZATION/RADIOFREQUENCY Reported series RR ~ 50% CHEMOTHERAPY Carcinoids < 10% RR ICC ~ 35-55 % RR INTERFERON-ALFA+/-SSA < 10% RR Analogs IFN Chemotherapy/RF/ 177 Lu Anti-hormonal effect Anti-proliferative effect <ul><li>PEPTIDE RECEPTOR RADIONUCLEOTIDE THERAPY </li></ul><ul><ul><li>[ 177 Lu],Tyr3-octreotate </li></ul></ul><ul><ul><li>RR (RECIST): 47%. SD:35% </li></ul></ul><ul><ul><li>TP: 36 mesos </li></ul></ul>
  9. 9. Impact of Somatostatin analogues in survival rate of metastatic carcinoids 1. Anthony LB, et al. Digestion. 1996;57(suppl 1):50–3. 2. Yao JC et al . J Clin Oncol 2008;26:3063–3072 Survival in patients with GEP-NETs and distant metastases was significantly longer 1988–2004 (post-octreotide) vs 1973–1987 (pre-octreotide)
  10. 10. PROMID: Evaluation of the antiproliferative effect of octreotide LAR <ul><li>P lacebo-Controlled, Double-Blind, Prospective, R andomized Study on the Effect of O ctreotide </li></ul><ul><li>LAR in the Control of tumour Growth in Patients with Metastatic Neuroendocrine MID gut tumours: A Report from the PROMID Study Group </li></ul><ul><li>Phase III, randomized, double-blind, placebo-controlled </li></ul><ul><li>18 centers in Germany (2001–2008) </li></ul><ul><li>Patients with midgut NETs </li></ul><ul><li>Treatment-naïve </li></ul><ul><li>Histologically confirmed </li></ul><ul><li>Locally inoperable or metastatic </li></ul><ul><li>Well-differentiated </li></ul><ul><li>Measurable (CT/MRI) </li></ul><ul><li>Functioning or non-functioning </li></ul>Octreotide LAR 30 mg im every 28 days Placebo im every 28 days RANDOMIZATION (1:1) Treatment until CT/MRI documented tumour progression or death Month 3 6 9 12 15 18 Rinke A, et al. J Clin Oncol. 2009 Oct 1;27(28):4656-63
  11. 11. Octreotide LAR 30 mg significantly extends TTP compared with placebo Time (months) Based on the ITT analysis 67% reduction in the risk of tumour progression HR=0.33; 95% CI: 0.19–0.55; P =0.000017 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Proportion without progression Time (months) Octreotide LAR: 42 patients / 27 events Median 15.6 months [95% CI: 11.0–29.4] Placebo: 43 patients / 41 events Median 5.9 months [95% CI: 5.5–9.1] Arnold R. Abst # 4508 presented at ASCO 2009, Orlando FL Rinke A et al. J Clin Oncol 2009;Aug 24 [Epub ahead of print]
  12. 12. Capdevila J & Salazar R. Target Oncol. 2009 Targeting signaling pathways in NETs
  13. 13. <ul><li>Increase the analog spectrum </li></ul><ul><ul><ul><li>SOM 230 </li></ul></ul></ul><ul><li>Antiangiogenics & Multiple Receptor Tyrosine Kinase Inhibitors </li></ul><ul><ul><ul><li>Bevacizumab </li></ul></ul></ul><ul><ul><ul><li>Chemotherapy + Targeted Therapy </li></ul></ul></ul><ul><ul><ul><li>Sunitinib , sorafenib, vatalanib, motesanib, pazopanib... </li></ul></ul></ul><ul><ul><ul><li>Thalidomide </li></ul></ul></ul><ul><ul><ul><li>Others: Endostatin, Atiprimod... </li></ul></ul></ul><ul><li>Mammalian target of rapamycin inhibitors </li></ul><ul><ul><ul><li>CCI-779 </li></ul></ul></ul><ul><ul><ul><li>RAD001 </li></ul></ul></ul>Promising New Targets in NET
  14. 14. hsst 1 0.93 ± 0.12 180 ± 20 280 ± 80 9.3 ± 0.1 30 hsst 2 0.15 ± 0.02 0.54 ± 0.08 0.38 ± 0.08 1.0 ± 0.1 0.4 hsst 3 0.56 ± 0.17 14 ± 9 7.1 ± 1.4 1.5 ± 0.3 5 Lanreotide Octreotide SOM 230 Octreotide/SOM 230 Compound hsst 4 1.5 ± 0.4 230 ± 40 >1000 >100 – hsst 5 0.29 ± 0.04 17 ± 5 6.3 ± 1.0 0.16 ± 0.01 40 Bruns C et al. Eur J Endocrinol . 2002;146:707-716 CI 50 in nM SRIF-14 Affinity of Somatostatin analogues for human 5 Sst subtypes
  15. 15. SOM 230 (Pasireotide) Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octeotride LAR: preliminary results of a Phase II study Kvols L, ASCO ’06. ClinicalTrials.gov database <ul><li>Symptomatic control in 12/44 pts (27%) </li></ul><ul><ul><li>Within a dose range of 600-900 µg bid </li></ul></ul><ul><li>3 pts  complete response </li></ul><ul><li>9 pts  partial response </li></ul><ul><li> Phase III study of Pasireotide vs Octeotride LAR in patients with advanced carcinoid disease (NCT00690430 ) </li></ul><ul><ul><ul><li>Pasireotide LAR 60 mg im vs Octeotride LAR 40 mg im </li></ul></ul></ul><ul><ul><ul><li>Primary endpoint: improvement carcinoid symptoms (bowel movements and flusing) </li></ul></ul></ul><ul><ul><li>Phase I study of Pasireotide in combination with RAD001 in patients with advanced neuroendocrine tumors (NCT00804336) </li></ul></ul>Ongoing Trials
  16. 16. Overexpression of VEGF is associated with poor prognosis in well differentiated neuroendocrine carcinomas Phan AT ASCO 2006 Antiangiogenic approach
  17. 17. Capdevila J, et al. Target Oncol. 2009 Antiangiogenic approach
  18. 18. Adapted from Phan and Yao, Oncology 2008 Antiangiogenic approach Agent (s) Target(s) Type of trial Tumor ORR Outcomes Comments Bevacizumab BV + CHT VEGF FOLFOX/XELOX/Temozolamide Phase II Carcinoid GEPNET 18% 20-30% 16.5 mo (PFS) Ongoing phase III Sunitinib VEGFR1-3, PDGFR, RET, FLT3, KIT Phase II Phase III Carcinoid PNETs 2% 17% 10.5 mo (TTP) 7.7 mo (TTP) Positive phase III Sorafenib VEGFR2-3, PDGF, Raf, KIT, RET Phase II Carcinoid PNETs 7% 17% 7.8 mo (PFS) 11.9 mo (PFS) - Vatalanib VEGFR1-3, PDGFR, KIT Phase II GEPNET 0% NR Ongoing Pazopanib VEGFR, PDGFR, Phase II GEPNET - - Ongoing Motesanib VEGFR, PDGFR, RET Phase II GEPNET - - Ongoing Atiprimod Inhibits VEGF secretion Deactivates Akt & STAT3 Phase II GEPNET 0% 76% at 6 mo (TTP) Ongoing Thalidomide T + CHT VEGF & bFGF Temozolamide Phase II GEPNET 0% 7-45% 80% SD rH-Endostatin Endogenous endothelial inhibition Phase II GEPNET 0% - -
  19. 19. Phase III, Randomized, Double-Blind Trial of Sunitinib vs Placebo in Patients with Progressive, Well-Differentiated, Malignant Pancreatic Islet Cell Tumors RANDOM I ZAT I ON N=340 <ul><li>Eligibility criteria </li></ul><ul><li>Well‑differentiated, malignant pancreatic islet cell tumor </li></ul><ul><li>Disease progression in past 12 months </li></ul><ul><li>Not amenable to treatment with curative intent </li></ul><ul><li>Balanced by region </li></ul><ul><li>Europe, Asia, Americas </li></ul>Sunitinib 37.5 mg/day orally, continuous daily dosing* Arm A Placebo* Arm B Primary endpoint: PFS Secondary endpoints: OS, ORR, DR, TTR, Safety, PRO 1:1 *With best supportive care Sunitinib in advanced pancreatic NETs Raymond E, et al. ASCO GI 2010
  20. 20. Study stopped on recommendation of an independent Data Monitoring Committee Raymond E, et al. ASCO GI 2010
  21. 21. modified from Cancer Cell Review 2007 The PI3-K/Akt/mTOR signaling pathway
  22. 22. Breast NET Colon Lung Kidney p-Akt, 42% PTEN, 15%–41% HER2, 30%–36% PI3-K, 18%–26% EGFR, 6% TSC1/TSC2 IGF-1/IGF-1R VHL, 33%-65% Ras, 40% p-Akt, 46% PTEN, 10% PI3-K , 20% EGFR, 8% HER2, 3% EGFR, 32%–60% p-Akt, 23%–50% Ras, 30% PTEN, 24% HER2, 5% PI3-K , 4% TGF  /TGF  1, 60%–100% VHL, 30%–50% IGF-1/IGF-IR, 39%-69% p-Akt, 38% PTEN, 31% TSC1/TSC2 The PI3-K/Akt/mTOR pathway is frequently deregulated in human cancer
  23. 23. The mTOR activation is involved in the pathogenesis of NETs 1. Von Wichert G, et al. Cancer Res. 2000;60:4573-81. 2. Van Gompel JJ, Chen H. Surgery. 2004;136:1297-302. 3.Yao JC. Best Pract Res Clin Endocrinol Metab. 2007;21:163–172. 4. Hobday TJ et al. Proc Am Soc Clin Oncol. 2003;22:269 <ul><li>Increased incidence of NETs in TSC and NF hereditary syndrome with constitutively activated mTOR </li></ul><ul><li>NF1 gene loss & TSC1/TSC2 mutations are associated with NETs 1,2 </li></ul><ul><li>Inherited von Hippel-Lindau disease (VHL) loss has been observed in islet cell tumours; 3 sporadic VHL loss contributes to carcinoid and islet cell tumours 4 </li></ul><ul><li>IGF-1 and IGF-1R are expressed in NET cells 1 </li></ul><ul><li>The PI3K/Akt/mTOR pathway is activated by IGF-1 in NET 1,2 </li></ul><ul><li>Loss of PTEN has been observed in cases of islet-cell carcinoma 3 </li></ul><ul><li>Angiogenesis is also controlled by mTOR pathway </li></ul>
  24. 24. mTOR inhibitors tested in GEP NETs Agent Drug Company Target & mechanism Type of trial Response Rate Reference Temsirolimus (CCI-779) Wyeth mTOR Protein kinase inhibitor Phase II Carcinoid Islet cell 4,8 % 6,7 % >70% SD (Duran et al., BJC 2006) Everolimus (RAD001) Novartis mTOR Protein kinase inhibitor Phase II (MDACC) Carcinoid Islet cell Islet cell (Radiant 1) 17 % 27 % 6.8 % (Yao et al., JCO 2008) (Yao et al, JCO 2010)
  25. 25. Phase II-III studies of RAD001 in GEP NETs RADIANT TRIALS (RAD 001 I n A dvanced N euroendocrine T umors) Study Population (n) Desig Primary End Point Study Status MDACC Islet cell tumors Single-arm, Response rate Results (Phase II) Carcinoids stratified Study Population (n) Design Primary End Point Study Status RADIANT-1 (2239) Islet cell tumors failing chemotherapy (144) Single-arm, stratified (Phase II) Response rate Results RADIANT-2 (2237) Carcinoid (Sandostatin) (420) Randomized placebo-RAD (Phase III) PFS, symptoms Accrued RADIANT-3 (2324) Islet cell tumors (300 – 350) Randomized placebo-RAD (Phase III) PFS Accrued
  26. 26. RADIANT-1: Study design <ul><li>Advanced pancreatic NET with RECIST progression following cytotoxic chemotherapy </li></ul><ul><ul><li>Stratum 1: No octreotide LAR 60 days prior to enrollment; received everolimus 10 mg/d </li></ul></ul><ul><ul><li>Stratum 2: Octreotide LAR ≥ 3 months prior to enrollment receive everolimus 10 mg/d + octreotide LAR (≤ 30 mg, q 28 d) </li></ul></ul>Stratum 1 115 patients SCREEN Stratum 2 45 patients <ul><li>Primary Endpoint </li></ul><ul><li>RR stratum 1 </li></ul><ul><li>Secondary Endpoint </li></ul><ul><li>RR stratum 2 </li></ul><ul><li>Response duration </li></ul><ul><li>Safety </li></ul><ul><li>PFS </li></ul><ul><li>Survival </li></ul><ul><li>PK </li></ul>Everolimus and octreotide LAR Everolimus Yao J, et al. J Clin Oncol. 2010 Jan 1;28(1):69-76
  27. 27. RADIANT-1: Best Percentage Change in Tumor Size (Central Radiology Review) Best % Change From Baseline (Measurable Lesions) Stratum 1: Everolimus (n=108) -100 -75 -50 -25 0 25 50 75 100 +++++++ ORR by central review 9.6% with 67.8% SD Best % Change From Baseline (Measurable Lesions) Stratum 2: Everolimus + Octreotide LAR (n=38) ORR by central review 4.4% with 80% SD -100 -75 -50 -25 0 25 50 75 100 + + + + + + + * ? 77.4% Clinical Benefit 84.4% Clinical Benefit Yao J, et al. J Clin Oncol. 2010 Jan 1;28(1):69-76
  28. 28. RADIANT-1: Progression-free Survival (Central Radiology Review) Everolimus 0 20 40 60 80 100 0 2 4 6 8 10 12 Time, mo Probability, % Patients at risk 45 39 32 18 15 7 3 Everolimus + octreotide LAR N = 45 Median PFS = 16.7 mo 0 20 40 60 80 100 0 2 4 6 8 10 12 Time, mo Probability, % Yao J, et al. J Clin Oncol. 2010 Jan 1;28(1):69-76 N = 115 Patients at risk 115 111 79 47 41 16 6 Median PFS = 9.7 mo
  29. 29. RADIANT-1: Overall Survival (Central Radiology Review) Everolimus Everolimus + octreotide LAR N = 115 Median survival = 24.9 months 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 Time, mo Pts at risk 115 111 105 91 71 41 21 9 4 0 Probability, % Median survival = Not reached N = 45 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 Time, mo Pts at risk 45 44 41 40 31 24 12 5 2 0 Probability, % Yao J, et al. J Clin Oncol. 2010 Jan 1;28(1):69-76
  30. 30. Take Home Messages <ul><li>NETs are an increasing incidence disease and are the second most prevalent type of GI malignancy </li></ul><ul><li>Heterogeneous tumors that need predictive and prognostic classifications (WHO, TNM, ENETS…) </li></ul><ul><li>Early diagnosis is essential to reduce the high percentage of metastatic disease at diagnosis </li></ul><ul><li>Limited therapeutic options are available for the management of NETs </li></ul><ul><li>Angiogenic and mTOR inhibition approaches have shown promising activity mainly in pancreatic NETs tumors </li></ul><ul><li>Although response rates are still <20%, high percentages of stabilizations and clinical benefit and also prolonged PFS have been observed </li></ul>
  31. 31. Take Home Messages <ul><li>A word of caution is needed to interpret the high percentages of disease stabilizations that have been shown in all of these phase II trials due to the slow growing nature of the majority of GEP-NETs. </li></ul><ul><li>Future clinical trial design must include: </li></ul><ul><ul><li>Documented disease progression as an inclusion criteria is needed for a correct evaluation of disease stabilization </li></ul></ul><ul><ul><li>phase III, placebo control trials are required to validate a real stabilization effect </li></ul></ul><ul><li>Running parallel to drug development, a biomarker development program would be of special interest. </li></ul><ul><li>Multitargeted combinations, combinations with classical cytotoxic drugs or hormonal therapy is warranted based on recently preliminary data. </li></ul>
  32. 32. Thank you so much!!

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