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Novel Targets and Treatment Approaches for GEP-NETs
New Frontiers and Treatment Advances for Metastatic Enteropancreatic Neuroendocrine Tumors Novel Targets and Treatment Approaches for GEP-NETs Focus on Mechanism of Action and Rationale for Use of Somatostatin Analogues (SSAs) and Other Novel Therapies in GEP-NETs
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Somatostatin and Somatostatin Receptors
Somatostatin (SST, SST-14) is a naturally occurring 14 amino acid peptide with endocrine, autocrine, and paracrine functions. Prosomatostatin (SST-28) has 28 amino acids, and preprosomatostatin has 120 amino acids. Universal endocrine “off-switch.” Inhibits the release of growth hormone and gastrointestinal hormones. Inhibits proliferation of neuroendocrine cells.
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Somatostatin and Somatostatin Receptors
The action of somatostatin is mediated through membrane bound receptors (SSTR). 5 subtypes of SSTR have been recognized (SSTR1-5), with SSTR2 subclassified into SSTR2A and SSTR2B These G protein-coupled receptors receptors (GPCRs) internalize after agonist activation. GPCR down-regulation and decreased mRNA and receptor protein synthesis can lead to development of resistance to treatment with somatostatin analogs. Somatostatin and its analogs induce G1 cell cycle arrest and induce apotosis in NET cells. This property can be exploited for therapy.
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Octreotide: A Somatostatin Analogue
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Somatostatin Receptor (sst) Binding Affinity of Somatostatin Analogues (SSA)
Agent sst1 sst2 sst3 sst4 sst5 Mean Receptor Binding Affinity (IC50 nmol/L) Somatostatin 0.9 0.2 0.6 1.5 0.3 Octreotide 280.0 0.4 7.1 >1000 6.3 Lanreotide 180.0 0.54 14.0 230.0 17.0 Pasireotide 9.3 1.0 >100 Bruns et al. Eur J Endocrinol. 2002;146(5):
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Primary endpoint: time to tumor progression
Placebo-Controlled, Double-Blind, Prospective Randomized Study of the Effect of Octreotide LAR in the control of tumor growth in patients with Metastatic Neuroendocrine Midgut Tumors (PROMID) Octreotide LAR 30 mg i.m. every 4 weeks Placebo i.m. every 4 weeks Continuation of treatment if no progression Informed consent Randomization 1:1 Month -1 3 6 9 12 15 18 Screening Primary endpoint: time to tumor progression Treatment was continued until CT or MRI documented tumor progression (WHO) Follow-up until death CT and/or MRI was evaluated by a blinded central reader No observation period prior to treatment to judge spontaneous tumor growth Arnold, et al ASCO GI Cancer Symposium, Abstract # 121
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Patients with tumor load ≤10% Patients with tumor load >10%
Octreotide LAR Significantly Increases TTP When Hepatic Tumor Load ≤10% Patients with tumor load ≤10% Patients with tumor load >10% Octreotide LAR: 32 patients / 18 events Median TTP months Placebo: 32 patients / events Median TTP months 0.25 0.5 0.75 1 6 12 18 24 30 36 42 48 54 60 Proportion without progression Time (months) Octreotide LAR: 10 patients / 8 events Median TTP months Placebo: 11 patients / 10 events Median TTP 5.45 months 0.25 0.5 0.75 1 6 12 18 24 30 36 42 48 54 60 66 72 78 Proportion without progression Time (months) Based on the ITT analysis Stratified log-rank test P<0.0001; HR=0.26 [95% CI: 0.14–0.50] Stratified log-rank test P=0.345; HR=0.64 [95% CI: 0.25–1.63] Arnold, et al ASCO GI Cancer Symposium, Abstract # 121
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Lanreotide Autogel A novel somatostatin analog with high affinity binding to SSTR2. The lanreotide molecule has hydrophobic and hydrophilic regions. At high concentrations in water, the molecules spontaneously assemble into stable structures. The hydrophobic regions bind, forming homo-dimers that link as chains organized into nanotubes. After subcutaneous injection, self-assembly reverses, releasing lanreotide, with % of drug released by 80 days. Suitable for giving higher and potentially more effective doses in a small volume. Better tolerated by thin or cachectic individuals than I.M. injections More reliable blood levels in obese individuals. Clinical trials of lanreotide autogel 120 mg SQ q 4 wk vs. placebo SQ q4 wk in non- functioning and in functioning carcinoid tumors have led to recent FDA approval and will be discussed in detail in this meeting.
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CLARINET: Primary Efficacy Endpoint (PFS)
Progression-free survival (ITT population*) 3 6 9 12 18 24 27 10 20 30 40 50 60 70 80 90 100 Patients alive and with no progression (%) Time (months) 62% 22% Lanreotide 120 mg vs. PBO P <0.001 HR=0.47 [95% CI: 0.30, 0.73] Lanreotide 32 events, 101 patients Median PFS not reached Placebo 60 events,103 patients Median PFS= 18.0 months [95% CI: 12.1, 24.0] 101 94 84 78 71 61 103 87 76 59 43 40 Numbers of patients at risk of death or PD 26 Data are from the ITT population. P-value derived from stratified log-rank test; HR derived from Cox proportional hazards model. HR, hazard ratio; ITT, intention to treat; PBO, placebo; PD, progressive disease; PFS, progression-free survival. Caplin ME, et al. N Engl J Med. 2014;371(3):
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Pasireotide High affinity binding to sst1, sst2, sst3, and sst5.
Hyperglycemia more frequent than with octreotide or lanreotide. Trial in functioning pancreatic NET is ongoing. Phase I MTD study of pasireotide LAR in NET is ongoing.3 In Phase 2, pasireotide improved carcinoid syndrome in 25% of octreotide-resistant patients.1,2 Randomized SOM-C2303 trial of pasireotide 60 mg vs. octreotide LAR 40 mg has recently been completed. 4 Symptom control rate (primary endpoint) was the same in both arms.4 Progression-free survival (secondary endpoint) was longer with pasireotide at 11.8 months vs 6.8 months with octreotide. Hazard ratio = 0.46, P = (log-rank test)4 1) Wolin, E et al, 2009 Am Soc Clin Oncol, Abstr. 122 2) Bruns C, et al. Eur J Endocrinol. 2002; 146: 3) Wolin, EM,. Endocr Rev, Vol. 34: MON-332 4) Wolin, E et. al.J Clin Oncol 31, 2013 (suppl; abstr 4031
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Peptide Receptor Radionuclide Therapy (PRRT)
From: Oberg. Theranostics 2012;2:448-58
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NET PRRT with 177Lu-DOTATATE
Beta comprises approximately 90% of the energy. These 133 KeV electrons penetrate 2 mm in tissue. Physical T1/2 of the electrons is 6.7 days. Less collateral damage than with 90Y therapy. Less kidney damage than with 90Y therapy. Gamma comprises approximately 10% of the energy output. Gamma (2 peaks, at 113 and 208 KeV) allows for somatostatin receptor scintigraphy (SRS) in addition to therapy.
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NET PRRT with 90Y-DOTATOC
935 KeV electrons penetrate 12 mm in tissue. Physical T1/2 of the electrons is 2.7 days. The higher energy electrons result in a “cross-fire” effect. This can kill cells in large heterogeneous tumors which cannot be directly targeted. More collateral damage around tumors. More kidney injury than other PRRT isotopes.
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New Directions in Targeting the Somatostatin Receptor
Treatment of NET with the Radiolabeled Somatostatin Analog [177Lu-DOTA0,Tyr3]Octreotate, 200 mCi IV every 6 to 10 weeks (Peptide Receptor Radiiotherapy or PRRT)1 Toxicity analysis (504 pts), and efficacy analysis (310 pts) Complete response in 2%, partial response 28%, and minimal response in 16%. Progression-free survival (PFS) was 40 months. Toxicity: If creatinine <1.8, and amino acid infusion used, kidney injury rare. MDS in 3.6%. Reversible liver injury 2 patients. NETTER-1 Study: Inoperable, progressive, OctreoScan positive, well-differentiated small bowel carcinoid on Octreotide LAR at a fixed dose for at least 12 weeks. Randomized Phase 3 trial of 177Lu-DOTA0-Tyr3-Octreotate plus Octreotide LAR 30 mg Q 4 wk vs. Octreotide LAR 60 mg Q.4 wk. 1) Kwekkeboom et al, J Clin Oncol May 1;26(13):
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Octreoscan vs. 68Ga-DOTA-TOC PET vs. 18F Bone scan
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Peptides and Receptors in Image-Guided Therapy: Theranostics of Neuroendocrine Neoplasms R. Baum et al. Semin Nucl. Med 42: (2012)
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