Winship Cancer Institute of Emory University New Treatments for Neuroendocrine Cancers George Fisher, MD, PhD Professor of Medicine Stanford University School of Medicine Disclosures • Contracted research support from: • Genentech, Bristol ‐ Myers Squibb, Ipsen, Eli Lilly, Polaris, X ‐ Biotech, and New Link • Fees for non ‐ CME services: Pharmaceutical Research Associates • Stock ownership: Seattle Genetics (spouse) 1
Topics NET 101: the basics Biological “targets” –Somatostatin receptors –mTOR –Angiogenesis Chemotherapy Liver directed options Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 3 3 3 Topics NET 101: the basics Biological “targets” –Somatostatin receptors –mTOR –Angiogenesis Chemotherapy Liver directed options Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 4 4 4 2
“Rare-omas” Site Incidence (per 100,000) Incidence is low Lung 1.35 Thymus 0.02 # diagnosed per year per 100,000 people Stomach 0.30 Small intestine 0.86 Colon 0.36 Appendix 0.15 Rectum 0.86 Pancreas 0.32 Liver 0.04 Other / unknown 0.74 Total 5.00 Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 5 5 5 Increasing Incidence Yao et al JCO ‘08 Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 6 6 6 3
Increasing Incidence Octreotide Approved Yao et al JCO ‘08 Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 7 7 7 Not really that rare… Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 8 8 8 4
Imaging Issues with NETs Non-contrast scan Arterial phase scan Venous phase scan Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 9 9 9 NET Path: Grading System NET (ENETS, WHO) Grade Designation <2 mitoses/10hpf Low grade AND <3% Ki67 index Well-differentiated 2-20 mitoses/10hpf Intermediate grade OR 3-20% Ki67 index >20 mitoses/10hpf High grade Poorly-differentiated OR >20% Ki67 index Adapted from: Klimstra DS, et al: Pancreas 39:707–712, 2010. Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 10 10 10 5
NET Biology 5 somatostatin receptors (SSTR 1-5 ) 80% NETs over-express SSTR 2 , followed by SSTR 1 and SSTR 5 Octreotide has high affinity for SSTR 2 Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 11 11 11 Radiolabelled somatostatin: imaging Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 12 12 12 6
Radiolabelled somatostatin: imaging Octreoscan image Krenning EP et al. Somatostatin receptor scintigraphy with [ III In-DTPA-D-Phe 1 ]- an [ 123 ]-Ty 3 ]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med . 1993;20(8):716-731. Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 13 13 13 Radiolabelled somatostatin: imaging 68 Ga-DOTATATE PET 111 In-octreotide Octreoscan Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 14 14 14 7
Targeting the Somatostatin Receptors Function SST 1 SST 2 SST 3 SST 4 SST 5 Antisecretory Anti-angiogenic Antiproliferative/ Inhibition of cell cycle Induction of apoptosis Adapted from Susini C, Buscail L and Weckbecker G, Lewis I, Albert R, et al. 1 References: 1. Weckbecker G, Lewis I, Albert R, et al. Nature Rev Drug Discov . 2003, 2:999-1017. 2. Öberg K, Kvols L, Caplin M, et al. Ann Oncol . 2004; 15:966-973. 3. Susini C, Buscail L. Ann Oncol . 2006; 17:1733-1742. Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 15 15 15 Somatotatin Analogs: Octreotide PROMID STUDY IN MIDGUT CARCINOID R Octreotide LAR A 30 mg IM q4wks Primary Endpoint N N=42 85 patients with D Time to Progression well-differentiated O metastatic midgut Secondary Endpoints M NETs I Overall Survival Z Placebo IM q4wks Response Rates E N=43 Overall Survival Time to Progression Octreotide Placebo p=0.000072, HR 0.34 (95% CI 0.20-0.59) Median OS not yet reached Arnold, GI ASCO 2009, abstract #121. Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 16 16 16 8
Somatostatin Analogs: Lanreotide CLARINET STUDY IN GEP-NETS (MIDGUT + PANCREATIC NETS) Primary endpoint: Progression Free Survival (n=204) 100 Lanreotide Autogel vs. placebo p=0.0002 HR=0.47 [95% CI: 0.30, 0.73] Patients alive and with no progression (%) 90 80 70 Lanreotide Autogel 120 mg 62% 60 32 events / 101 patients median, not reached 50 Placebo 40 60 events / 103 patients median, 18.0 months [95% CI: 12.1, 24.0] 30 20 22% 10 0 0 3 6 9 12 18 24 27 Time (months) P-value derived from stratified log-rank test; HR derived from Cox proportional hazard model. HR, hazard ratio; ITT, intention-to-treat. Caplin et al, ESMO Annual Meeting Amsterdam 2013 Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 17 17 17 Peptide Receptor Radionuclide Therapy Retrospective Analysis Key Inclusion: Octreoscan positive, Karnofsky performance status >50% 504 patients (1772 total treatments) 310 patients available for analysis Results Median Overall Survival = 46 months; Median Progression-free Survival = 33 months Toxicities: Mostly acute and subacute (nausea, vomiting, abdominal pain, hair loss); rare serious delayed (renal insufficiency, liver toxicity, myelodysplastic syndrome) Responses 3 Months After Last Administration of 177 Lu-Octreotate (n=310) Tumor type Response Minor Response Stable Progressive n (%) n (%) n (%) n (%) Carcinoid 42(23) 31 (17) 78 (42%) 37 (20%) Pancreas NET 30 (42%) 13 (18%) 19 (26%) 10 (14%) Other 19 (38%) 7 (14%) 10 (20%) 14 (28%) Total 86 (28) 51 (16) 107 (35) 61 (20) Kwekkeboom, JCO , 2008: 2124. Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 18 18 18 9
Current Trial: PRRT with 177 Lu-DOTA Phase III: NETTER-1 Trial 1 ° endpoint PFS 177 Lu-DOTA 0 -Tyr 3 - Advanced, Octreotate progressive, + Octreotide LAR somatostatin R receptor positive, midgut carcinoid tumours Octreotide LAR 60 mg Sponsor: Advanced Accelerator Applications, France Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 19 19 19 Future Attempts at Targeting SSTR: 177 Lu-DOTA-JR11: SSTR2 antagonist –Wolfgang Weber @ Memorial Sloan Kettering Nanoparticle delivery targeting SSTR2 –Herb Chen @ University of Wisconsin Adeno-associated viral construct targeting SSTR2 –Renata Pasquilini @ MD Anderson Immunologic targeting of SSTR2 with CAR-T cells –David Metz et al @ University of Pennsylvania Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 20 20 20 10
Targeting the mTOR pathway VEGF Growth Factors VEGFR PI3-K Integrins PTEN PI3-K LKB1 Nutrients AMPK Amino Acids Akt/ Akt/ ILK PKB PKB TSC1/TSC2 mTOR RAD001 RAD001 Energy mTOR RAD001 FKBP-12 FKBP-12 4E-BP1 P S6 S6K1 elF-4E Protein Production Reduced VEGF Production Reduced Reduced Cell Growth and Reduced Gene Reduced Proliferation Proliferation Transcription Cell Growth Cancer Cell Endothelial Cell Bjornsti M-A, Houghton PJ. Nat Rev 2004;4:335 Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 21 21 21 Targeting mTOR in PNETs: Ph III Everolimus (RADIANT 3) Advanced pancreatic Median PFS NETs Everolimus11.0 mo n=410 Placebo 4.6 mo P<0.001 R Placebo Everolimus Yao. NEJM.2011. N=203 10 mg qd N=207 FDA approved for Pancreatic NET Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 22 22 22 11
Targeting mTOR in non-pancreatic NETs: Ph III Everolimus (RADIANT 2) Advanced carcinoid PFS by Central Review n=429 Everolimus 16.4 mo Placebo 11.3 mo R Everolimus 10 mg Placebo + + Octreotide Octreotide LAR LAR Best Percentage Change from Baseline N=216 N=213 Pavel. Lancet, Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 23 23 23 2011 Recently Completed Trial Targeting mTOR: Phase III RADIANT 4 1 ° endpoint Progression Free Survival [closed to accrual] Advanced, Everolimus + BSC progressive, somatostatin receptor R positive, GI and lung Best Supportive Care carcinoid tumours Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 24 24 24 12
Angiogenesis as a Target Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 25 25 25 Taking Advantage of Hypervascular Features of NETs Ligand Receptor Tumor Cells Interaction Angiogenic Factors Proliferation Invasion and Migration Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 26 26 26 13
New blood vessels grow due to Receptor Mediated Signaling Pathway VEGF VEGF-C VEGF-D Flk-1/KDR (VEGFR-2) P PLC P Kinase Activation Cascade Growth, Migration, Endothelial Cell Permeability, Anti-apoptosis Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 27 27 27 New blood vessels grow due to Receptor Mediated Signaling Pathway VEGF VEGF-C VEGF-D Bevacizumab Flk-1/KDR (VEGFR-2) P PLC P Kinase Activation Cascade Growth, Migration, Endothelial Cell Permeability, Anti-apoptosis Stanford Cancer Center Stanford Cancer Center Stanford Cancer Center 28 28 28 14
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