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Ongoing and Future Clinical Investigation in GEP Nens

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Ongoing and Future Clinical Investigation in GEP Nens ESMO PRECEPTORSHIP PROGRAMME Multidisciplinary management, standards of care and future perspectives Lugano, Switzerland 13-14 April 2018 CHAIR: Nicola Fazio, Italy SPEAKERS: Pier Luigi Filosso, Italy George Pentheroudakis, Greece Andrea Frilling, United Kingdom Rocio Garcia-Carbonero, Spain Massimo Milione, Italy Marianne Pavel, Germany Aviral Singh, Germany Anders Sundin, Sweden Christos Toumpanakis, United Kingdom LEARNING OBJECTIVES Ongoing• Toand learn about future best clinical practice clinical in the multid isciplinary management of gastroenteropancreatic (GEP) and thoracic neuroendocrine neoplasms (NEN) patients Oncology investigation in GEP NENs of • To learn about the biological and clinical principles of diagnostic and therapeutic strategy Institute • To understand the importance of terminology, pathological and clinical classification, morphological and functional characterization of disease European Nicola Fazio, M.D., Ph. D. • To learn how to manage the integration of several different therapies in patients with advanced disease • To learn how to apply into clinical practice information coming from medical literature, guidelines and recommendations Division of Gastrointestinal Medical Oncology and ACCREDITATION Neuroendocrine Tumors EuropeanThe programme Institute of this event of has Oncology been accredited with 10 ESMO-MORA category 1 points. RecertificationMilan, is necessary Italy for medical oncologists to remain professionally certified by ESMO. Recertification guarantees that a certified medical oncologist has continued to update her/his knowledge and continues to possess the necessary skills and standards for the practice of medical oncology. For further details, please refer to esmo.org. ACKNOWLEDGEMENTS This event is supported by an unrestricted educational grant from ORGANISATION AND CONTACTS ESMO Head Office Education Department Via Luigi Taddei 4 6962 Lugano - Viganello Switzerland Email: [email protected] www.esmo.org Disclosure! Novartis, Ipsen, Pfizer, AAA, Merck Serono: consulting and advisory services! Novartis, Merck Serono: Research funds (to the institution) ! Investigation lines in GEP NENs • SSA • Sequence • PRRT • High grade • New drugs • Immunotherapy Investigation lines in GEP NENs • SSA • Sequence • PRRT • High grade • New drugs • Immunotherapy Efficacy and Safety of Lanreotide Autogel® 120 mg Administered Every 14 Days in Well Differentiated, Metastatic or Locally Advanced, Unresectable Pancreatic or Midgut Neuroendocrine Tumours Having Progressed Radiologically While Previously Treated With Lanreotide Autogel® 120 mg Administered Every 28 Days CLARINET FORTE Histopathologically confirmed, grade 1 or 2, metastatic or locally advanced, unresectable pNET (pNET cohort) or midgut NET (midgut cohort) with or without hormone related syndromes, with a proliferation index (Ki67) ≤20%. Positive somatostatin receptors type 2 100 patients European, prospective, multicentre, double-blind randomised study evaluating lanreotide Lanreotide as Maintenance Therapy in Patients With Non-Resectable Duodeno-Pancreatic Neuroendocrine Tumors (REMINET) Inclusione criteria: Documented stable disease or objective response after first-line treatment (chemotherapy or biotherapy for 6 months), within 4 weeks (28 days) prior to randomisation Treatment: Lanreotide 120 mg every 28 days until disease progression versus placebo Investigation lines in GEP NENs • SSA • Sequence • PRRT • High grade • New drugs • Immunotherapy GETNE-1206 (SEQTOR): Phase III Study in Patients With AdvancedGETNE 1206 (SEQTOR) pNET phase III trial Compare efficacyin andpaents safety of with everolimusadvanced followed panNETsby chemotherapy with STZ + 5-FU upon progression, or theenrolling reverse sequence (chemotherapy with STZ + 5-FU followed by everolimus upon progression) Arm A: Everolimus Everolimus Progression STZ + STZ + Arm B: 5-FU 5-FU Primary end point: rate of second PFS at 84 weeks of treatment Unpublished data. Clinicaltrials.gov ID, NCT02246127. 26 Investigation lines in GEP NENs • SSA • Sequence • PRRT • High grade • New drugs • Immunotherapy A prospective, randomised, Controlled, Open-label, Multicentre phase III study to evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide compared to targeted molecular therapy with Everolimus in patients with inoperable, progressive, somatostatin receptor- positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP- NET). COMPETE trial 177Lu-edotreotide G1-G2 advanced progressive GEP NET Rand. Phase III Everolimus COMPETE: 177Lu-Edotreotide vs. Everolimus 4. Approval Status & Timelines COMPETE Worldwide Initiated & Sites Ready for Initiation ‰ Australia, Austria, France, Germany, Netherlands, South Africa, Switzerland, UK Review in progress ‰ Italy, Poland EC / CA submissions to be done ‰ US COMPETE_Newsletter 4_Jan2018 4 Investigation lines in GEP NENs • SSA • Sequence • PRRT • High grade • New drugs • Immunotherapy Phase II trial Everolimus and Temozolomide in Advanced GEP NECs (G3) Histologically proven neuroendocrine carcinoma with a Ki67 of 20-55%. Primary GEP NET or unknown primary where metastases are mainly abdominal Randomized phase II study of cisplatin and etoposide versus temozolomide and capecitabine in patients (pts) with advanced G3 non-small cell gastroenteropancreatic neuroendocrine carcinomas (GEPNEC): A trial of the ECOG-ACRIN Cancer Research Group (EA2142). G3 (only large cell) GEP NEC CDDP / VP-16 Ki-67 21-100% First-line Rand. Phase II 126 pts CAP / TEM Prospec;ve Internaonal Phase II Mul;-centre Trial 177Lu-DOTA-octreotate (LuTate) PRRT Vs Capecitabine Temozolomide chemotherapy for Grade 3 GEP NEN (Ki67 20-55%) – LUCAT Trial PI: Grace Kong, Michael Michael, Rod Hicks Peter MacCallum Cancer Center, Melbourne, Australia • Primary objec;ve –PFS. • 56 paents • 1st or 2nd line Investigation lines in GEP NENs • SSA • Sequence • PRRT • High grade • New drugs • Immunotherapy Novel TKIs in GEP NETs Compound VEGFR PDGFR FGFR CSF1R KIT FLT-3 RET MET 1 2 3 α β Sunitinib ✔ ✔ ✔ ✔ ✔ ✔ ✔ Pazopanib ✔ ✔ ✔ ✔ ✔ ✔ Cabozantinib ✔ ✔ ✔ ✔ ✔ ✔ Lenvatinib ✔ ✔ ✔ ✔ ✔ ✔ ✔ Sulfatinib ✔ ✔ ✔ ✔ ✔ ✔ Sulfanib in GEP NET 81 NET pts (41 pNET) Jia, ENETS 2017, Oral presentation Sulfanib in GEP NET Jia, ENETS 2017, Oral presentation Cabozannib in GEP NET PR 15% 41 carcinoids SD 63% mPFS 31 mo Phase II trial PR 15% 20 pNETs SD 75% mPFS 22 mo Chan et al., ASCO GI 2017, Poster TALENT trial Phase II with LENVATINIB in GEP NETs § Pancreatic G1/G2 cohort (n=55) Lenvatinib binds to RET, VEGFR and FGFR § Gastrointestinal G1/G2 cohort (n=55) Review of safety and effcacy of axitinib This IC50 is 10-fold lower for the VEGF family of in y1.4 fold accumulation compared to single admin- receptors than for other TKIs such as pazopanib, suni- istration. The oral bioavaibility of axitinib is 58%. tinib, or sorafenib.26–28 Concerning other non-VEGF Although a low pH results in the highest solubility tyrosine kinase receptors (PDGF, fbroblast growth of axitinib, studies have demonstrated that the effect factor, colony-stimulating factor), the IC50 of axi- of pH on absorption of axitinib was not clinically tinib was 1.6 to 1000 nmol/L (versus 6–880 nmol/L signifcant. As a measure of precaution, antacids with other agents).29 These results testify to the high or proton pump inhibitors should be administered potency and selectivity of axitinib against VEGFRs at times other than 2 h before and 2 h after drug (Table 1).26–28 Blockade of the VEGFR induces major dosing.11 Axitinib is highly bound (99%) to human changes of tumor vasculature in mouse models. In plasma proteins with preferential binding to albu- vivo, dynamic contrast enhanced magnetic resonance min and moderate binding to A1-acid glycoprotein. imaging (DCE-MRI), which is an imaging technique The plasma half-life ranges between 2.5 and 6.1 h that can measure the density, integrity, and leakiness and a steady-state is attained within 15 days. Linear of tissue vasculature, showed that axitinib decreases correlations have been reported between dose and the tumor blood fow/permeability. Maximum reduc- maximum plasma concentration, in addition to area tion in tumor endothelial transfer constant (Ktrans)— under plasma concentration-time curve.16 The mean an indicator of vascular leakage to the extracellular apparent volume of distribution in patients receiving space—was observed on day 7 after dosing and was 5 mg twice daily was 160L.11 Axitinib is primarily correlated with decreased micro-vessel density, cel- metabolized in the liver by cytochrome P450 (CYP) lular viability, and tumor growth. 3A4 and to a lesser extent by CYP1A2, CYP2C19, uridine diphosphate glucuronosyl-transferase (UGT) Metabolism and pharmacokinetic profle 1A1, and the drug transporters P-glycoprotein. Two Pharmacokinetic analyses have been obtained from metabolites are produced: an N-glucuronide metabo- polled data of 17 trials, in both healthy volunteers lite and a sulfoxide. Both are 400-fold less potent and cancer patients.11 A two-compartment disposi- against VEGFR-2 in vitro than axitinib.11 Less than tion model with frst-order absorption and lag-time one percent of the absorbed drug remained unchanged adequately describes the axitinib concentration- in the urine. Otherwise, a recent meta-analysis found time profle. After a single dose of 5 mg in the fed no statistically signifcant associations between the state, axitinib is rapidly absorbed with peak plasma polymorphism of genes encoding these enzymes and concentrations
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