Nets 2008 Carlos F Pinto

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review of neuroendocrine tumors treatment

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Nets 2008 Carlos F Pinto

  1. 1. New Frontiers in Neuroendocrine Tumors Treatment Carlos Frederico Pinto Instituto de Oncologia do Vale Hospital Regional do Vale do Paraiba 2008
  2. 2. Neuroendocrine Tumors - Background Carcinoid, islet cell carcinoma Slow growing, often metastatic at diagnosis Associated with carcinoid syndrome caused by hypersecretion of biogenic amines, peptides and polypeptides and manifested mainly with diarrhea and flushing Symptoms are treated with somatostatin analogues (Octreotide & Lanreotide)
  3. 3. Somatostatin analogues
  4. 4. Octreotide High binding affinity for the somatostatin receptor subtype sst2, and low affinity for sst3 and sst5 receptors Many patients respond to Octreotide but subsequently experience tachyphalyxis after 12- 18 months May be due to downregulation of sst2 receptors on tumor cells or overexpression of other somatostatin receptors
  5. 5. OCTREOTIDE MECHANISMS OF ACTION Affinity to SST-2 A & B receptors Indirect effects: Inhibition of hormone secretion (GF, insulin, prolactin, intestinal peptid) Inhibition of growth factor secretion (IGF, Somatomedines 1 and 2, EGF, PDGF, TGF-alfa) Inhibition of angiogenesis Immunomodulation Direct effect Antimitotic Induction of cell death (at high doses) Lamberts et al. Endocrinol Rev 1991;12:450-82
  6. 6. SOMATOSTATIN ANALOGUES Octreotide – Sandostatin ® Sandostatin LAR ® Lanreotide – Somatuline ® SOM-230 – Pasireotide RC-160 – Vapreotide – Octastatin ®
  7. 7. OCTREOTIDE FOR TREATMENT OF NET Somatostatin analogues provide: Symptomatic response: 70 % Biochemical response: 30-50 % Tumor control: 3% Di Bartolomeo, Cancer, 1996.
  8. 8. SOMATOSTATIN ANALOGUES Natural somatostatin has a half-life of 3 minutes. Rebound phenomenon can be observed in withdrawal. Sandostatin (octreotide) is a long acting analogue with a half-life of 100 minutes and can be used sc/iv. Sandostatin LAR (long acting, repeatable) is a depot form used intramuscularly every 3-4 weeks Study No.of Treatment Symptomatic Tumor pts response regression Tomasetti 16 Ocreotide LAR 15/16 0 (14 SD, 2 PD) Aliment Pharmacol 20 mg Ther 2000
  9. 9. OCTREOTIDE – ADVERSE EVENTS Flatulance Nausea-vomitting Abdominal pain tachyphalyxis after Diarrhea 12-18 months Lipid malabsorption Biliary malfunction Cholelitiasis Vitamin D malabsorption Injection site pain Hypothyroidism Hypo/hyperglycemia Cardiac arrithmias The dose should be adjusted in patients using insulin, oral hypoglicemic agents, beta blocker and calcium channel blockers
  10. 10. USE OF OCTREOTIDE IN NETs SC for 2 weeks If tolerated and provides symptom relief: Sart Sandostatin LAR at 20 mg i.m. / Every 4 week SC form should be continued for another 2 weeks Patient should be reevaluated 3 months later If symptoms are under control patient can be treated with 10 mg Sandostatin LAR every 4 weeks İf symtoms are persisitant the dose can be increased to 30 mg SC sandostatin can be used as salvage
  11. 11. Combination of Interferon + Octreotide Response rate Objective response CR : %0 PR : %0 SD : % 75 PD : % 25 Biochemical response CR : %0 PR : % 77 SD : % 18 PD : %5 Tiensuu Eur J Cancer 1992;28A:1647-50
  12. 12. Abstract 171 Safety and Efficacy of Pasireotide (SOM230) in Patients with Metastatic Carcinoid Tumors Refractory or Resistant to Octreotide LAR: Results of a Phase II Study L. Kvols, M.D. H. Lee Moffitt Cancer Center and Research Institute
  13. 13. Pasireotide (SOM230) Novel, multi-ligand somatostatin analogue High affinity binding to four of the five somatostatin receptor subtypes: sst1, sst2, sst3 & sst5 Compared to Octreotide has a 30-, 5- and 40- times greater affinity for sst1, sst3 & sst5 & comparable affinity for sst2
  14. 14. Study Design Phase II, multicenter, open label Patients with carcinoid symptoms refractory to Octreotide LAR Pasireotide 300mcg SQ bid Doses escalated to 1200mcg SQ bid
  15. 15. Safety & Tolerability Related to Adverse Event Total (n) Study Drug (n) Nausea 12 12 Abdominal Pain 14 9 Diarrhea 10 3 Vomiting 3 2 Fatigue 10 3 + Weight loss & hyperglycemia
  16. 16. Results – Symptom Control 12/44 Patients with improvements in either BM/day and/or No. of flushing episodes/day
  17. 17. Pasireotide - Conclusions Effective in controlling carcinoid symptoms in 27% patients refractory to Octreotide Well tolerated with a safety profile similar to Octreotide
  18. 18. TUMOR TARGETED RADIOACTIVE SOMATOSTATIN TREATMENT Alpha-emitting radioligands Short acting auger electrons are used 111 In-pentetreotide Beta-emitting radioligands High energy beta particules 90Y-DOTA0 Tyr3-octreotide (OctreoTher) 177Lu-DOTA0 Tyr3-octreotate 90Y-lanreotide Can only be used in sst2 and sst5 (+) NET de Herder et al, Curr Opin Oncol, 2002
  19. 19. New agents mTOR TKI
  20. 20. Abstract 178 Phase II Study of RAD001 (Everolimus) and Depot Octreotide (Sandostatin LAR) in Patients with Advanced Low Grade Neuroendocrine Carcinoma J. C. Yao, M.D. University of Texas, M.D. Anderson Cancer Center ASCO 2007
  21. 21. NET - RAD001 Octreotide LAR 30mg IM q28 days + RAD001 5mg PO daily 26 patients (16 carcinoids, 11 islet cell) 4 PR and 19 SD, 10 ↓ CgA Toxicity Mild apthous ulceration G3/4: anemia, thrombocytopenia, apthous ulcer, diarrhea, edema, fatigue, hypoglycemia, nausea, pain, rash
  22. 22. Phase 2 Study of RAD001 and Depot Octreotide Single-arm phase 2 Metastatic or unresecatable well-differentiated NET RAD001 dose Patient 1-30: 5mg daily Patient 31-60: 10 mg daily Sandostatin LAR 30mg IM 28d At 12 weeks, CT/MRI Yao J. et al. PASCO 25:198 , 2007 (#4503)
  23. 23. Gary K. Schwartz, ASCO 2007
  24. 24. Study objectives Assess objective tumor response rate as defined by RECIST Assess PFS Assess biochemical response rate Assess safety of RAD001 at 5 and 10mg per day with Sandostatin LAR 30mg every 4 weeks Yao J. et al. PASCO 25:198 , 2007 (#4503)
  25. 25. Efficacy (RECIST): by tumor type: Overall Carcinoid Islet cell N = 60 N=30 N=30 PR 12 (20%) 4(13%) 8(27%) SD 43(72%) 25(83%) 18(60%) PD 5(8%) 1(3%) 4(13%) Median 59 wks 64 wks 50 wks PFS Yao J. et al. PASCO 25:198 , 2007 (#4503)
  26. 26. Compare mTOR with sandostatin alone response Carcinoid Islet cell Overall RAD001 + sando 4/30(13%) 8/30(27%) 12/60(20%) LAR (Yao, ASCO 2007) Phase II 1/21(5%) 1/15(7%) 2/37(5%) Temsirolimus (Duran, BJC 2006) Phase II 2/28(8%) 0/5(0%) 2/31(6%) Sando LAR (Wymenga, JCO 1999)
  27. 27. Why it works? IGF-1 and IGF-1R are expressed and IGF- 1 activates AKT and mTOR Pathways in NET cells Wichert G, Cancer Res, 2000. RAPALOGs blocks signaling pro growth, proliferation and survival: Rapamycin RAD001 CCI-779
  28. 28. Gary K. Schwartz, ASCO 2007
  29. 29. Gary K. Schwartz, ASCO 2007
  30. 30. Gary K. Schwartz, ASCO 2007
  31. 31. Gary K. Schwartz, ASCO 2007
  32. 32. Gary K. Schwartz, ASCO 2007
  33. 33. Gary K. Schwartz, ASCO 2007
  34. 34. Gary K. Schwartz, ASCO 2007
  35. 35. Gary K. Schwartz, ASCO 2007
  36. 36. Rationale for combination mTOR inhibition activates AKT, a survival pathway by a negative feedback loop. Sandostatin LAR normalizes IGF-1 levels in patients with acromegaly Sandostatin inhibits AKT in the exocrine pancreas. So... Sandostatin should block ATK activation by “Rapalogues”
  37. 37. IGF-1R Inhibitors Sandostatin IMC-A12: MoAB BMS-536924: TKI CP751,871: MoAB R1507: MoAB
  38. 38. Sorafenib in NETs – Background NETs overexpress VEGF,VEGF-R, PDGF and PDGF-B Overexpression of VEGF associated with inferior PFS Increased Ki-67 is associated with inferior outcome Hobday T, PASCO 25:198 , 2007 (#4504)
  39. 39. Eligibility Well or moderatily differentiated NET Thyroid, Pheoc. and adrenal excluded Measurable disease ECOG PS 0-2 <= prior chemotherapy Prior embolization allowed No prior antiangiogenic therapy Prior or concurrent octreotide allowed Hobday T, PASCO 25:198 , 2007 (#4504)
  40. 40. Design Sorafenib 400mg po BID Primary endpoint is confirmed PR by RECIST criteria Secondary endpoints: Minor response Progression free at 6 months Median PFS, OS Toxicity Two stage Phase II Hobday T, PASCO 25:198 , 2007 (#4504)
  41. 41. Results: objective response Total CT ICC N=77 N=42 N=35 Confirmed PR 9% 7% 11% (any PR) (12%) (7%) (17%) Confirmed MR 10% 7% 14% (20-29% decrease) Hobday T, PASCO 25:198 , 2007 (#4504)
  42. 42. Results: progression and survival Median follow up for survivors 8.5 months 65% progression free at 6 months CT =58% ICC = 72% 16 have died, OS not mature Biochemical response: 6 out of 13 with CT had reduction in 5-HIAA Hobday T, PASCO 25:198 , 2007 (#4504)
  43. 43. Translational Results: VEGFRs VEGFR VEGFR p-value 0-1+ 2-3+ VEGFR2 33% 7.4% 0.06 % responders (PR) (4/12) (2/27) VEGFR3 18.2% 5.9% 0.36 % responders (PR) (4/22) (1/17) Ki67 <2% Ki67 >2% % responders (PR) 0.0% 22.2% 0.08 (6/27) Hobday T, PASCO 25:198 , 2007 (#4504)
  44. 44. Efficacy of VEGF Pathway Inhibitors in Neuroendocrine Tumors Tumor response rate Median Agent Target Patients (%) PFS VEGFR,PDG FR, c-Kit, 41 carc 2 42 Sunitinib 1 RET 61 (PET) 15 33 Bevacizumab 2 VEGF 18 carcin 17 NR 1. Kulke et al, Proc ASCO 2005 A4008 2. Yao et al, Proc ASCO 2005 A4007
  45. 45. New agents Temozolomide Bevacizumab
  46. 46. Kulke MH, PASCO 25:198 , 2007 (#4505)
  47. 47. Kulke MH, PASCO 25:198 , 2007 (#4505)
  48. 48. Kulke MH, PASCO 25:198 , 2007 (#4505)
  49. 49. Kulke MH, PASCO 25:198 , 2007 (#4505)
  50. 50. Kulke MH, PASCO 25:198 , 2007 (#4505)
  51. 51. Kulke MH, PASCO 25:198 , 2007 (#4505)
  52. 52. Kulke MH, PASCO 25:198 , 2007 (#4505)
  53. 53. ADVANCES IN NETS TREATMENT AT A GLANCE DISEASE STABILIZATION PARTIAL RESPONSES OR PROLONGING PFS: MINOR RESPONSES PROLONGATION OF Bortezomib PSF(RECIST) Pasireotide (SOM-230) Bevacizumab + temozolomide POSSIBLE Bevacizumab STABILIZATION Temozolomide Endostatin Sorafenib Thalidomide Sunitinib Gefinitib Temsirolimus Imatinib Everolimus (RAD001)
  54. 54. CONCLUSION Significant progress has been observed in the treatment and understanding of the pathobiology and genetics of these neoplasms. New drugs with multiple mechanisms of action have significant activity, with improvements in response and PFS in phase II trials Several phase III trials are accruing patients using mTOR and TK inhibitors agents. It´s a “work in progress”....

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