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
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4. GEP-NETs Are the Most Prevalent NETs Modlin IM, Lye KD, Kidd M. Cancer . 2003;97(4):934-959.
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. 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
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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)
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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. Capdevila J & Salazar R. Target Oncol. 2009 Targeting signaling pathways in NETs
16. Overexpression of VEGF is associated with poor prognosis in well differentiated neuroendocrine carcinomas Phan AT ASCO 2006 Antiangiogenic approach
17. Capdevila J, et al. Target Oncol. 2009 Antiangiogenic approach
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% - -
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20. Study stopped on recommendation of an independent Data Monitoring Committee Raymond E, et al. ASCO GI 2010
21. modified from Cancer Cell Review 2007 The PI3-K/Akt/mTOR signaling pathway
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
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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. 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
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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. 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. 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
Good morning ladies and gentlemen, Mr Chairman, It’s a real pleasure for me to be here this morning and I would like to thank to the organizing committee for inviting to discuss what I think it’s an amazing topic: neuroendocrine tumors. As you will see neuroendocrine tumors are not as rare as you can imagine and the future in this field is at least promising.
NETs arise from enterochromaffin cells that are located throughout the body and constitute a heterogeneous group of tumors that really generates a clinical challenge. NETs can produce a hormone related syndrome or be non-functional, and we can find them in the whole body: GI tract, islet cells of the pancreatic gland, pheocromocytomas and paragangliomas are also NETs, carcinoids of the lung well-differentiated or small cell carcinomas, and also tumors with neuroendocrine characteristics in the kidney, bladder, breast, protate, thymus…
In the last 30 years the incidence of NETs have shown a significant increasing in incidence mainly for lung, small intestine and rectum but also for the other locations.
The most frequent organ where you find a NET is the lung, but you consider the body systems, the GI tract involves the majority of NET cases, being ileum and colorectal the most frequent. Regarding GI tract malignances, NETs are the second most prevalent neoplasm, after the colorectal cancer.
The first classification of NETs was proposed by Williams and Sandler at the early sixties, divided the NETs regarding their embryological origin in foregut, midgut and hindgut. Between this classification and the currently most used, the WHO classification, several ones have been proposed. As I said, nowadays, the most used is the WHO classification that you can see in this slide, that classify neuroendocrine tumors in three main catherogies, well-differentiated tumors and carcinomas, with main differences in biological behaivor, the capability to produce metastases, the Ki67 index, the size and the angioinvasion, the the thrid group clearly different are the poorly differentiated neuroendocrine tumors, with the main characteristic of high proliferation index, mostly measured by the Ki67 index. Several other classifications are currently being evaluated, such as the ENETS or the TNM classifications, but are still in process of validation.
One of the big problems of NETs is the delay in the diagnosis. There are not specific signs or symptoms related to NETs, and the clinical presentation of a neuroendocrine tumor has a wide possible differential diagnosis. Symptoms like sweating, flushing, diarrhea and intermittent abdominal pain are common of many other disorders, such as fucntional bowel diasese, anxiety menopause or much others as you can see in this slide. This situation leads to a median delay in the diagnosis of more than 5 years.
As you can imagine with this delay, most of patients will be diagnosed with distant metastases, in same cases in more than 70% of cases, and this fact will jeopardize the overall survival of our patients. Here you can see the median overall survival expected for patients regarding the extension of the disease, and you can see the significant differences between groups.
The main treatment for NETs is surgery and no adjuvant therapies have demonstrated as useful in this setting. For the metastatic disease, we have several options as you can see in this slide. Surgery maintains an important role for the treatment of metastatic disease, mainly for the resection of liver mets, achieving 5-y survivals higher than 60% or 80 % in case of complete resections. The liver transplantation is widely discussed and only could be evaluated in special cases. For unresectable disease, classical options have included locoregional liver treatments, such as embolizations or RF, that achieve response rates around 50%, the chemotherapy, more effective in pancreatic NETs than in carcinoids, the biological therapy with SSA and IFN, alone or in combination, with limited antitumor activity and more antihormonal effects, and more recently the treatment with radionucleotides, not widely available, with promising results in some reports that could achieve near 50% of responses, but still not compared with conventional approaches.
What could not be discussed is the impact of SSA in the natural history of NETs significantly increasing the overall survival of patients with carcinoid tumors.
One of the main questions that have been recently resolved is the potential antiproliferative effect of SSA. The PROMID trial randomized patients with advanced midgut carcinoids to receive Octeotride LAR or placebo.
The study was stopped after a preplanned interim analysis because of the significant benefit obtained in time to progression for patients that received octeotride, with median TTP for patients treated with placebo of less than 6 months compared to more than 15 months in patients treated with octreotride LAR, with a HR of 0.33. The results of this trial have demonstrated the antiproliferative effects of SSA mainly by tumor stabilizations. Only 2% of RR was observed.
But when we look to the future not only in NETs but also in whole oncology the most important approach is to target some deregulated points in the cellular signalling pathways with the aim of be more specific and less toxic.
Several promising new targets are being under investigation. There is a new drug that increase the spectrum of action of SSA, several antiangiogenic drugs and inhibitors of the mammalian target of rapamycin.
In this table you can see the affinity of SSA Lanreotide and Octeotride, with the main activity through receptors types 2, 3 and 5. The new drug SOM230 is able to bind the receptors 2, 3 and 5 with a higher affinity, and also receptor type 1.
We have the results of a phase II trial that evaluated the efficacy of Pasireotide in patients with carcinoid tumors refractory to octeotride LAR, and showed a symptomatic control in 27% patients. There are two studies ongoing with pasireotide, one phase III trial that will compare pasireotide vs octeotride and a phase I trial that is evaluating the combination of pasireotide with the mTOR inhibitor RAD001, that I will discuss in the next slides.
Another important approach in NETs is the blockage of the angiogenesis process. We know that NETs have a rich vascularization and the overexpression of VEGF is associated with poor prognosis compared with patients that express VEGF.
Several drugs with antiangiogenic properties are under evaluation in NETs. You know all of these drugs that block the receptors of VEGF and also drugs such as bevacizumab that block the ligand VEGF.
Here in this table you can see all the studies that are ongoing with antiangiogenic drugs in NETs. We have the results of a phase II study with bevacizumab with a response rate of 18% and a phase III ongoing phase III trial. We also have data of activity of the combination of bevacizumab with oxaliplatin-based chemotherapy, but also with other drugs such as sorafenib or thalidomide alone and in combination with chemotherapy. Other antiangiogenic drugs such as motersanib or pazopanib are currently in phase II studies.
The first antiangiogenic compound that will reach the clinical practice is sunitinib after the results of this phase III trial that randomized patients with progressive pancreatic NETs to receive sunitinib at a continuous daily dosing vs placebo.
After a preplanned analysis, the study was stopped due to the significant differences observed in PFS in favor of sunitinib that doublet the mPFS from 5.5 months to 11.4 months, with a HR of 0.4.
Another important pathway related with several tumor tumor types and also NETs is the PI3K-AKT-mTOR pathway. Several membrain receptors can activate the pathway that finally activates the two complexes of mTOR controlling cell cycle, growth and survival, but also angiogenesis regulating the hypoxia inducible factor 1. PI3K-AKT-mTOR could be activated thought several growth factors, but also mTOR could be activated by several stress situations, such as hypoxia or energy deprivation like glucose or aminoacid concentration decrease. When AKT is activated previous activation of PI3K and regulated by PTEN phosphorilates the tuberous sclerosis complex that it’s a main tumor supressor protein kinase in this pathway that finally activates the first mTOR complex discovered, the mTORC1 also known as rapamycin and nutrien-sensitive multiprotein complex. This multiprotein complex is formed by at least 4 proteins, with its main two compounds are the catalytic component, mTOR, and the RAPTOR protein (regulatory associated protein of mTOR). The two main effectors of mTORC1 are S6K1 and 4E-BPI that regulate mRNA translation and cell growth. But mTOR is also the catalytic compound of a second multiprotein complex, known as mTORC2 and often called the “rapamycin-insensitive complex”, formed of at least 5 proteins, which the most important is RICTOR (rapamycin-insensitive companion of mTOR). The upstream of mTORC2 is unclear but is known that can phosphorilate Akt and the downstream cascade that leads to cell growth, proliferation and survival. As I mentioned before, mTORC2 is not sensitive to nutrients or rapamycin and this evidences that rapamycin does not inhibit all of mTOR’s functions. Additionally, mTOC1 regulates HIF1alfa that targets the VEGF genes regulating angiogenesis.
The PI3K.AKT.mTOR pathway is frequently derregulated in human cancer. Several mutations have been described in membraine receptors, but also mutations in PI3K, amplifications of AKT and losses of function of several tumor supressor genes, such as PTEN or the VHL gene. Several mechanisms for the constitutive activation of the pathway have been found in a range of human cancers. These include amplification or mutations of PI3K (colon, breast, ovary or pancreas ), amplifications of Akt ( ovary and breast ), loss of the p hosphatase and ten sin homologue deleted on chromosome 10 ( PTEN ); and more often sustained activation or over-expression of cell surface growth factor receptors, such as h uman e pidermal growth factor r eceptor and Insulin like Growth Factor. In the cancers shown, signaling through mTOR is stimulated by defects in one or more of several pathway components upstream of mTOR (growth factor receptors, PI3-K, Akt, PTEN, TSC1/TSC2) or by stimulation of PI3-K by mutant Ras/Raf/MAPK pathway components. In certain types of renal cell cancer and some neuroendocrine tumors, loss of function of VHL eliminates the mechanism for clearance of hypoxia-inducible factor 1a (HIF-1a), resulting in the transcription of numerous “ hypoxia-associated” proteins, which drive angiogenesis and other cellular functions.
The mTOR activation is involved in the pathogenesis of NETs. The incidence of NETs is increased in TSC and NF that constitutively activates mTOR….
Two mTOR inhibitors have been studied for the treatment of NETs.
Here you can see the development program of RAD001 in NETs. The first two phase II studies has been already published, and the two phase III regulatory studies in carcinoids and in pancreatic NETs have completed their recruitment and results are expected in the near future.
Here you can see the results of the first international phase II clinical trial of RAD001 in pancreatic NETs, divided in 2 no randomized stratums, one with RAD001 at 10 mg/d and the other stratum with the combination of RAD001 plus octeotride LAR 30 mg/4w.
The objectives responses observed in both stratum were significantly lower compared with the first phase II study that reported more than 25% of responders by RECIST criteria. What we can see is the benefit in nearly 80% of patients with same percentage of tumor decrease although not reached the criteria for a PR.
Here you can see the PFS curves that seams, although is a phase II study, that the combination of RAD001 plus octeotride could be better than the use of RAD001 alone.
And this fact is also seen in for the overall survival, of 25 months in the stratum of RAD001 alone and not reached for the combination arm.
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