Displaying One Session

Cartagena Auditorium (Hall 3) Poster Discussion session
Date
30.09.2019
Time
10:30 - 11:30
Location
Cartagena Auditorium (Hall 3)
Chairs
  • Nicola Fazio (Milan, Italy)
  • Rocio Garcia-Carbonero (Madrid, Spain)
  • Sophie Leboulleux (VILLEJUIF, France)
Poster Discussion – NETs and endocrine tumours Poster Discussion session

1382PD - Relation between objective tumour shrinkage and progression-free survival (PFS) in the NETTER-1 population (ID 4991)

Presentation Number
1382PD
Lecture Time
10:30 - 10:30
Speakers
  • Marianne E. Pavel (Erlangen, Germany)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

NETTER-1 demonstrated that Radioligand Therapy (RLT) with LUTATHERA® significantly prolongs PFS in progressive midgut neuroendocrine tumor patients compared to 60 mg octreotide (Oct). In oncology, treatment efficacy has often been associated with early reduction of tumor size. As RLT differs from traditional treatments, we sought to verify whether objective tumor shrinkage predicts duration of PFS by assessing the relations between changes in lesion size and treatment efficacy, evaluated by PFS among NETTER-1 patients.

Methods

Post-hoc analyses were performed on the NETTER-1 population on local tumor imaging assessments on the full analyses set (n = 231) with data cut-off date on June 30th, 2016. The best response (change from baseline in sum of target lesion diameters) during 3 intervals after treatment onset was used as a covariate in a Cox regression, thus differentiating whether the time corresponds to an event or a censoring. One interval corresponded to 150 days, i.e. a month prior to 4th injection; 180 days matched the 4th injection and the last interval was set to no limit.

Results

For patients treated with Oct, Cox regression showed a HR of 0.914 [95% CI: 0.860 – 0.971], p = 0.0034. This suggests that the risk of disease progression decreases by 9% for each incremental percentage of shrinkage. Among the patients treated with Lu, Cox regression showed a HR of 1.006 [0.982 – 1.03] p = 0.6236, suggesting that LUTATHERA® prolonged PFS even when tumor objective response was undetected during treatment cycles. As a sensitivity, a 180-day-limit and no-limit (i.e. using the best response up to time of censoring/event) were also applied. With the 180-day-limit, HRs were 0.952 [0.904 - 1.003], p = 0.0652 and 1.013 [0.991-1.037], p = 0.2523 for Oct and Lu, respectively; similarly the no-limit, HRs were 0.952 [0.922, 0.982] p = 0.0023 and 1 [0.984, 1.017] p = 0.9713.

Conclusions

Durable response of LUTATHERA® treatment goes beyond objective tumor shrinkage. This study conveys crucial information on the patient’s management with respect to LUTATHERA®: treatment benefit of 4 cycles should not be assessed only by objective tumor shrinkage.

Clinical trial identification

NETTER-1: NCT01578239.

Legal entity responsible for the study

Advanced Accelerator Applications.

Funding

Advanced Accelerator Applications.

Disclosure

M.E. Pavel: Advisory / Consultancy: Novartis. P. Broberg: Full / Part-time employment: Advanced Accelerator Applications. M. Caplin: Advisory / Consultancy, Speaker Bureau / Expert testimony: Advanced Accelerator Applications. P. Ruszniewski: Speaker Bureau / Expert testimony: Advanced Accelerator Applications. P. Santoro: Full / Part-time employment: Advanced Accelerator Applications. L. Ravasi: Full / Part-time employment: Advanced Accelerator Applications. All other authors have declared no conflicts of interest.

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Poster Discussion – NETs and endocrine tumours Poster Discussion session

1383PD - Phase I study of CC-90011 in patients with advanced solid tumours (STs) and relapsed/refractory non-hodgkin lymphoma (R/R NHL) (ID 5796)

Presentation Number
1383PD
Lecture Time
10:30 - 10:30
Speakers
  • Antoine Hollebecque (Villejuif, France)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

CC-90011, a potent, selective, and reversible oral inhibitor of lysine-specific demethylase 1A, has shown antiproliferative activity against cancer cells in vitro and in patient (pt)-derived xenografts.

Methods

CC-90011-ST-001 is a phase I, first-in-human study of CC-90011 in ptswith advanced unresectable STs and R/R NHL. Pts received oral CC-90011 once a week (QW) in 28-d cycles. Primary endpoints included safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to evaluate preliminary efficacy, pharmacokinetics, and pharmacodynamics (PD).

Results

As of 24 Apr2019, 64 pts with advanced STs and 1 with R/R NHL were enrolled; 25 pts had neuroendocrine neoplasms (NENs) (majority grade 3). Data presented are as of 18 Jan 2019 (n = 50). Pts received escalating doses of CC-90011 at 1.25 (n = 4), 2.5 (n = 5), 5 (n = 6), 10 (n = 4), 20 (n = 5), 40 (n = 6), 60 (n = 6), 80 (n = 10), or 120 mg (n = 4). The nontolerated dose was established as 120 mg QW, the MTD as 80 mg QW, and the RP2D as 60 mg QW. Median age was 61 y (range, 22–75), 52% were men, and pts received a median of 3 (range, 1–9) prior anticancer regimens. Thrombocytopenia, an on-target effect, was the only dose-limiting toxicity. Grade 3/4 treatment-related adverse events (AEs) were thrombocytopenia (20%), neutropenia (8%; in the context of thrombocytopenia at the highest doses), and fatigue (2%). Serious AEs occurred in 21 pts (42%); 4 (8%) were treatment-related. Peak plasma concentrations occurred 2-4 h postdose and average terminal half-life was ∼71 h; exposure was dose proportional and with repeated QW dosing, limited accumulation of plasma exposures was observed. PD analysis showed decreased CgA and MMD in response to CC-90011. One pt with R/R NHL had a complete response (CR) (currently in cycle 19); 7 pts had stable disease (SD) ≥6 mo (1 pt with bronchial NEN is currently in cycle 29).

Conclusions

CC-90011 is well tolerated with promising antitumor activity in pts with advanced malignancies, including a durable CR in R/R NHL and prolonged SD in NENs. PD data showed significant target engagement. Further evaluation of CC-90011 in combination with other agents in advanced malignancies is warranted.

Clinical trial identification

NCT02875223; CC-90011-ST-001.

Editorial acknowledgement

Tisheeka Graham-Steed, PhD BioConnections, LLC.

Legal entity responsible for the study

Celgene Corporation.

Funding

Celgene Corporation.

Disclosure

A. Hollebecque: Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Honoraria (institution): Eisai; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Servier; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Incyte; Advisory / Consultancy: Debiopharm; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: MedImmune. J.S. de Bono: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sierra Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Daiichi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genmab; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: GSK; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Menarini Silicon Biosystems; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Orion; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Taiho; Research grant / Funding (institution): Cellcentric; Research grant / Funding (institution): Celgene. R. Plummer: Honoraria (self): Ellipses; Advisory / Consultancy: Pierre Faber; Advisory / Consultancy: Genmab; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy: Octimet; Advisory / Consultancy, Licensing / Royalties: Clovis Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Karus Therapeutics; Advisory / Consultancy: Biosceptre; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Cybrexa; Advisory / Consultancy: Sanofi Aventis; Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Speaker Bureau / Expert testimony: Tesaro; Travel / Accommodation / Expenses: MSD. J. Capdevila: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Advanced Accelerator Applications; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Research grant / Funding (institution): Celgene. G. Curigliano: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self): Novartis; Honoraria (self): SEAGEN; Advisory / Consultancy: BMS. V. Moreno: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Regeneron; Speaker Bureau / Expert testimony: Bayer/Loxo. F.G.M. De Braud: Advisory / Consultancy: TizianaLife Sciences; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: Octimet Oncology; Advisory / Consultancy: Incyte; Advisory / Consultancy: Teofarma; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Loxo Oncology; Research grant / Funding (institution): Tesaro; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Gentili; Speaker Bureau / Expert testimony: Fondazione Menarini; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Noema S.r.l.; Speaker Bureau / Expert testimony: ACCMED; Speaker Bureau / Expert testimony: Dephaforum S.r.l.; Speaker Bureau / Expert testimony: Nadirex; Speaker Bureau / Expert testimony: Biotechspert Ltd; Speaker Bureau / Expert testimony: Prime Oncology. P. Martin-Romano: Research grant / Funding (institution), Non-remunerated activity/ies: AstraZeneca; Research grant / Funding (institution), Non-remunerated activity/ies: BMS; Research grant / Funding (institution), Non-remunerated activity/ies: Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution), Non-remunerated activity/ies: Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution), Non-remunerated activity/ies: Pfizer; Research grant / Funding (institution), Non-remunerated activity/ies: Roche; Research grant / Funding (institution): Sanofi; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: Johnson & Johnson; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: MedImmune; Non-remunerated activity/ies: NH TherAGuiX. J. Parra-Palau: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene, Inc. T. Sánchez Pérez: Full / Part-time employment: Celgene Corp. E. Filvaroff: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Celgene; Shareholder / Stockholder / Stock options: Amgen; Shareholder / Stockholder / Stock options: Gilead; Shareholder / Stockholder / Stock options: Genentech/Roche. M. Lamba: Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene Corp.; Licensing / Royalties: Pfizer. Z. Nikolova: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene Corp. All other authors have declared no conflicts of interest.

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Poster Discussion – NETs and endocrine tumours Poster Discussion session

1384PD - SUNitinib with EVOfosfamide (TH-302) for G1/G2 metastatic pancreatic neuroendocrine tumours (pNETs) naïve for systemic treatment. The SUNEVO phase II trial of the Spanish task force group for neuroendocrine and endocrine tumours (GETNE) (ID 3199)

Presentation Number
1384PD
Lecture Time
10:30 - 10:30
Speakers
  • Enrique Grande (Madrid, Spain)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

Sunitinib (SUN) is approved for the treatment of advanced progressive pNETs. Hypoxia induced by SUN could foster the activation of the prodrug evofosfamide (EVO), designed to release the DNA alkylator bromo-isophosphoramide mustard under hypoxic conditions. The SUNEVO trial seeks to exploit the potential synergy of SUN + EVO in advanced pNETs.

Methods

Phase-II, single-arm, multicenter trial that included 17 patients (pts) with metastatic G1/G2 pNETS naive for systemic treatment (tx) other than somatostatin analogues (SSA). Tx consisted on EVO 340 mg/m2 on days 8, 15 and 22 every 4 weeks (q4w), and sunitinib 37.5 mg/day continuously. Objective response rate (ORR) was selected as the primary endpoint and evaluated q8w by RECIST 1.1.

Results

Median age was 62.4 years, 41.2% had prior SSA, 47% had a Ki-67 >10%, 70.6% had liver involvement. Patients received a median of 5 (1-21) and 4 (0-21) cycles of SUN and EVO, respectively. After a median follow-up time of 15.7 months (m), 23.5% achieved a partial (N = 3) or complete response (N = 1), 11 pts had stable disease (64.7%) and 1 pt (5.3%) had progressive disease as best response. Median time to response was 1.9m (1.4-8.8) and duration of response was 18.5 m (4.2-38.3). Median PFS was 10.3 m (2.6-18.0). Treatment-related adverse events of >G3 or were observed in 52.9% pts, being the most frequent being neutropenia (18.8%), hypertension (12.5%), ALT increase (12.5%), thrombopenia (6.3%), and fatigue (6.3%). 4 pts (26.7%) discontinued at least one drug due toxicity.

Conclusions

SUN + EVO is active in pts with advanced pNETs, but the toxicity profile of the combination negatively affects tolerability. Biomarker analyses to select patients most likely to benefit from this therapy are ongoing.

Clinical trial identification

EUDRACT Number: 2014-004072-30 Approval date for the trial: 22-January-2015.

Editorial acknowledgement

Mfar Clinical Research S.L.

Legal entity responsible for the study

Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE).

Funding

Molecular Templates Inc. and Pfizer Inc.

Disclosure

E. Grande: Speaker Bureau / Expert testimony, Public speaking and expert: Pfizer, Ipsen, BMS, Eisai, Roche, MSD, Sanofi-Genzyme, Adacap, Novartis, Eusa Pharma, Pierre Fabre, Lexicon, Celgene; Leadership role, Principal Investigator: AstraZeneca, Pfizer, Ipsen, Mtem/Threshold Lexicon; Honoraria (institution), Medical Education Grant: MSD, Roche; Non-remunerated activity/ies, Advasory Board Member: Enets; Non-remunerated activity/ies, Directory Board Member: Getne; Non-remunerated activity/ies, Directory Board Member: Gethi. C. Lopez: Honoraria (self): Pfizer, Ipsen, Roche; Advisory / Consultancy: Pfizer, Ipsen, Roche; Research grant / Funding (self): Pfizer, Ipsen, Roche; Travel / Accommodation / Expenses: Pfizer, Ipsen, Roche; Honoraria (self): Novartis. T. Alonso Gordoa: Research grant / Funding (self): Roche; Travel / Accommodation / Expenses: Sanofi, Pfizer. J. Capdevila: Advisory / Consultancy: Eisai, Bayer, Exelixis, Novartis, Pfizer, Adacap, Merck Serono; Speaker Bureau / Expert testimony: Eisai, Bayer, Exelis, Ipsen, Novartis, Pfizer, Adacap, Merck Serono; Research grant / Funding (self): Eisai, Exelixis, Adacap, AstraZeneca, Novartis; Travel / Accommodation / Expenses: Ipsen, Pfizer, Eisai. A. Teulé: Advisory / Consultancy: Pfizer, Ipsen, Novartis. I. Sevilla: Advisory / Consultancy: Ipsen, Novartis, Pfeizer, Lilly; Travel / Accommodation / Expenses: Ipsen. P. Gajate: Advisory / Consultancy: IPSSEN; Speaker Bureau / Expert testimony: Ipsen; Travel / Accommodation / Expenses: Ipsen. J. Molina-Cerrillo: Speaker Bureau / Expert testimony: Ipsen, Janssen. J. Hernando Cubero: Speaker Bureau / Expert testimony: Eisai, Ipsen, Roche, Angelini Pharma; Travel / Accommodation / Expenses: Ipsen, Novartis, Advanced Accekeratir Applications, Roche, AstraZeneca, Eisai. R. Garcia-Carbonero: Honoraria (self): Ipsen, Roche, Sanofi, BMS, Servier, Novartis, Pfizer, Merck, PharmaMar, Adacap; Honoraria (self), An intermediate Family Member: Merck, PharmaMar, Roche, BMS, AZ, Lilly, Boerhinger, Gilead Sc, Servier, Sysmex; Advisory / Consultancy: Ipsen, Novartis, Pfizer, AAA; Speaker Bureau / Expert testimony: Ipsen, Pfizer; Research grant / Funding (institution): Pfizer, BMS, MSD, AstraZeneca; Travel / Accommodation / Expenses: Roche, Merck. All other authors have declared no conflicts of interest.

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Poster Discussion – NETs and endocrine tumours Poster Discussion session

Invited Discussant 1382PD, 1383PD and 1834PD (ID 6890)

Lecture Time
10:30 - 10:45
Speakers
  • Nicola Fazio (Milan, Italy)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30
Poster Discussion – NETs and endocrine tumours Poster Discussion session

Q&A led by Discussant (ID 6893)

Lecture Time
10:45 - 10:50
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30
Poster Discussion – NETs and endocrine tumours Poster Discussion session

1385PD - New circulating biomarkers in gastro-entero-pancreatic-neuroendocrine-tumours (ID 5891)

Presentation Number
1385PD
Lecture Time
10:50 - 10:50
Speakers
  • Martine Bocchini (Meldola, Italy)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

Gastro-Entero-Pancreatic-Neuroendocrine-Tumors (GEP-NETs) overexpresses Somatostatine receptors (SSTRs). Peptide Receptor Radionuclide Therapy (PRRT) target SSTRs. Although GEP-NETs show SSTRs overexpression, about 30% of patients do not respond to PRRT. It has been demonstrated that 18FDG –PET, reflects higher glucose uptake and represent a prognostic marker in GEP-NETs. MiRNAs are involved several mechanisms, including cell metabolism. In this scenario it would be pivotal to find new prognostic and/or predictive markers able to correlate with 18FDG/PET status.

Methods

Platelet free plasma from 66 GEP-NET patients was collected. Whole miRNOME NGS analysis was performed on exome enriched small-RNAs fraction of 24 patients: 12 18PET/FDG+ and 12 18PET/FDG-. MiRNAs significantly associated with 18PET/FDG outcome were identified and validated by RT/qPCR on overall case series. Target miRNAs fold enrichment were then combined to create predictors (pAB, pAC, pBC and pABC). Man-Whitney test was applied and validated miRNAs were correlated with clinical outcome and parameters (ki-67, grading, tumor burden and 68Gallium-PET SUVmax).

Results

NGS profiling revealed 7 miRNAs able to distinguish 18FDG/PET positive from negative Pancreatic-NETs (PNETs). Mir-A, mir-B, mir-C (patent pending) had been then validated on overall case series by multiplex RT/qPCR (p < 0,0109, p < 0,0033 and p < 0,0002, respectively) on PNETs case series and pBC resulted to be the best predictor (p < 0,0002). All validated miRNAs and derived predictors, expecially mir-B, result significantly increased in small intestine (SINETs) and in PNETs patients when compared to healthy controls. Correlation analysis between target miRNAs and clinical parameters also revealed that mir-B negatively correlates with 68Ga-PET SUVmax (p < 0,0351).

Conclusions

We defined a 3 miRNAs signature able to correlate with 18FDG/PET status. Over expression of mir-A, mir-B, mir-C or combined predictors in PNETs with the same SSTR status might help to identify PRRT non-responders. In addition mir-B negatively correlates with clinical outcome and 68Ga-PET SUVmax. We are investigating if mirB interfere with SSTR expression, affecting PRRT efficacy.

Legal entity responsible for the study

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) Srl - IRCCS.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Discussion – NETs and endocrine tumours Poster Discussion session

1386PD - Longitudinal increase in Ki67 and high-grade transformation in pancreatic neuroendocrine tumours (PNETs) (ID 1590)

Presentation Number
1386PD
Lecture Time
10:50 - 10:50
Speakers
  • Johan Botling (Uppsala, Sweden)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

Tumor proliferation and grade are important prognostic factors at diagnosis of PNETs. Little is known about how these factors change over time and if longitudinal increase in Ki67-index is associated with prognosis. The purpose of this work was to describe longitudinal changes in Ki67-index and tumor grade, as well as its impact on overall survival, in PNETs.

Methods

Platelet free plasma from 68 GEP-NET patients was collected. Whole miRNOME NGS analysis was performed on exome enriched small-RNAs fraction of 24 patients: 12 18PET/FDG+ and 12 18PET/FDG-. MiRNAs significantly associated with 18PET/FDG outcome has been identified and validated by RT/qPCR on overall case series. Target miRNAs fold enrichment were then combined to create predictors (pAB, pAC, pBC and pABC). Man-Whitney test was applied and validated target miRNAs had been correlated with clinical outcome and clinical parameters (ki-67, grading, tumor burden and 68Gallium-PET SUVmax).

Results

NGS whole miRNOME analysis revealed 10 target miRNAs able to distinguish 18FDG/PET positive from negative Pancreatic-NETs (PNETs). Subsequently, mir-A, mir-B, mir-C (patent pending) have been validated on overall case series by multiplex RT/qPCR (p < 0,0047 and p < 0,0001, respectively), on PNETs case series and pBC and pABC resulted to be the best predictors (p < 0,0001). All validated miRNAs and derived predictors, especially mir-B, result significantly increased in small intestine (SINETs) and in PNETs patients when compared to healthy controls. Correlation analysis between target miRNAs and clinical parameters also revealed that mir-B negatively correlates with 68Ga-PET SUVmax (p < 0,04), suggesting interference with SSTR expression.

Conclusions

We defined a 3 miRNAs signature able to correlate with 18FDG/PET status. Over expression of mir-A, mir-B, mir-C or combined predictors in PNETs can provide prognostic information on tumor aggressiveness and might help to identify PRRT non-responders. In addition mir-B negatively correlates with clinical outcome and 68Ga-PET SUVmax. We are investigating if mirB interfere with SSTR expression, affecting PRRT efficacy.

Legal entity responsible for the study

Uppsala University.

Funding

European Neuroendocrine Tumor Society, Uppsala University.

Disclosure

J. Botling: Honoraria (self): Novartis. A. Lamarca: Honoraria (self): Merck; Honoraria (self): Pfizer; Honoraria (self): Ipsen; Advisory / Consultancy: EISAI; Advisory / Consultancy: Nutricia; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: AAA; Travel / Accommodation / Expenses: SirtEx; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Mylan; Travel / Accommodation / Expenses: Delcath. G. Rindi: Honoraria (self): Novartis; Honoraria (self): Ipsen. J. Crona: Honoraria (self): Novartis; Honoraria (self): Ipsen. All other authors have declared no conflicts of interest.

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Poster Discussion – NETs and endocrine tumours Poster Discussion session

Invited Discussant 1385PD and 1386PD (ID 6891)

Lecture Time
10:50 - 11:05
Speakers
  • Rocio Garcia-Carbonero (Madrid, Spain)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30
Poster Discussion – NETs and endocrine tumours Poster Discussion session

Q&A led by Discussant (ID 6894)

Lecture Time
11:05 - 11:10
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30
Poster Discussion – NETs and endocrine tumours Poster Discussion session

1862PD - Impact of lung metastasis on overall survival (OS) in the phase III SELECT study with lenvatinib (LEN) in patients (pts) with radioiodine refractory differentiated thyroid cancer (RR-DTC) (ID 3362)

Presentation Number
1862PD
Lecture Time
11:10 - 11:10
Speakers
  • Makoto Tahara (Kashiwa, Japan)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

In the randomized phase III SELECT study, LEN demonstrated a significant prolongation of progression-free survival compared with placebo (PBO) in pts with RR-DTC. There was no significant difference in overall survival (OS) between LEN and PBO arms which was likely due to > 80% of pts on the PBO arm crossing over to open-label LEN treatment. This exploratory post hoc analysis investigated the impact of measurable lung metastasis on OS from the SELECT study.

Methods

The hazard ratio (HR) for OS (data cutoff, September 1, 2016) and the 95% CIs were estimated using the Cox proportional hazards model. The influence of various baseline characteristics on OS was analyzed using a multivariate analysis based on a Cox proportional hazards model. Subgroup analysis of OS was conducted based on maximum size of measurable lung metastasis (≥ 1 cm per RECIST 1.1) at baseline.

Results

In the overall population (392 pts), median OS of LEN (261 pts) and PBO (131 pts, with 115 pts crossed over to LEN) arms, were 40.3 months (M) and 34.5 M, respectively (hazard ratio [HR] 0.87, 95% CI 0.66 –1.15, P = 0.3170). In 306 pts with lung metastasis of ≥ 1.0 cm, significant prolongation of OS was observed with LEN (199 pts) compared with PBO (107 pts, with 95 pts crossed over to LEN) (HR 0.63, 95% CI 0.47–0.85, P = 0.0025). This was maintained after adjustment for baseline characteristics in the multivariate model. Similar trends of OS prolongation by LEN were observed in pts with lung metastasis of ≥ 1.5 cm, ≥ 2.0 cm, and 1.0–2.0 cm (Table).

1862PD Overall survival by size of measurable lung metastasis at baseline

Lung LesionNumber of Pts
Median OS (M)
HR95% CIP Value
LENPBOLENPBO
≥1.0 cm19910744.733.10.630.47 – 0.850.0025
≥1.5 cm1508444.122.30.630.45 – 0.890.0082
≥2.0 cm945834.719.30.650.44 – 0.980.0383
1.0–2.0 cm1054949.238.60.630.40 – 0.990.0438

≥ 1 cm per RECIST 1.1

Conclusions

In pts with lung metastasis of ≥ 1.0 cm, LEN significantly prolonged OS compared to pts treated by PBO including those crossed over to LEN. This post-hoc analysis suggests that RR-DTC pts with lung metastasis could be candidates for targeted therapy.

Clinical trial identification

NCT01321554; Release date: December 30, 2016.

Editorial acknowledgement

Oxford PharmaGenesis, Newtown, PA, USA; Funded by Eisai Inc.

Legal entity responsible for the study

Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

M. Tahara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self): Merck Serono; Honoraria (self): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Boehringer-Ingelheim; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Novartis. N. Kiyota: Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Merck Serono; Honoraria (self), Research grant / Funding (institution): Astra-Zeneca; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Chugai Pharmaceutical. A..O. Hoff: Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Astra-Zeneca; Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Genzyme. T.K. Owonikoko: Advisory / Consultancy, Research grant / Funding (institution): Novartis, Celgene, Bayer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune, Abbvie; Advisory / Consultancy, Research grant / Funding (institution): G1 Therapeutics, Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Amgen, Loxo/Lilly; Research grant / Funding (institution): Astellas, Stemcentrx, Regeneron, Corvus Pharmaceuticals; Research grant / Funding (institution): United Therapeutics, Fujifilm, Pfizer; Research grant / Funding (institution): Aeglea Biotherapeutics, Incyte, Merck; Advisory / Consultancy: Sandoz, Eisai, Takeda, Seattle Genetics; Advisory / Consultancy: BerGenBio, PharmaMar, Boehringer Ingelheim; Advisory / Consultancy: EMD Serono, Xcovery; Advisory / Consultancy: Heron Pharmaceuticals, Armo BioSciences; Shareholder / Stockholder / Stock options: Cambium Oncology. C.E. Dutcus: Full / Part-time employment: Eisai Inc.. T. Suzuki: Full / Part-time employment: Eisai Co., Ltd. M. Ren: Full / Part-time employment: Eisai Inc.. S. Misir: Full / Part-time employment: Eisai Inc. L.J. Wirth: Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merck. All other authors have declared no conflicts of interest.

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Poster Discussion – NETs and endocrine tumours Poster Discussion session

1863PD - Prescription and treatment patterns of lenvatinib (L) in patients with radioactive iodine-refractory differentiated thyroid cancer (rDTC): A retrospective analysis of the Canadian Patient Support Program (PSP) (ID 3665)

Presentation Number
1863PD
Lecture Time
11:10 - 11:10
Speakers
  • Sebastien J. Hotte (Hamilton, Ontario, Canada)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

L provided a 19.4 month (mo) median PFS in the phase 3 Study of Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) and an objective response rate of 60.2%; however, all patients (pts) experienced some toxicity. In Canada, a PSP was created to offer L to pts with rDTC prior to public funding. We report the prescription practices and treatment patterns of these pts.

Methods

Between August 2015 and January 2019, 223 pts with rDTC started L as part of the PSP. Prescriber information, patient demographics, start and discontinuation dates, starting doses and dose modifications and reasons for discontinuation were ascertained whenever possible. Pt and prescriber demographic and clinical characteristics were described using summary statistics. Kaplan-Meyer method was used to estimate persistency on L, defined as time from first prescription to discontinuation.

Results

Two-hundred twenty-three rDTC pts were analyzed (42% female, mean age 63.4 years). Median study follow-up was 15.8 mo. Mean starting dose was 21.2mg and was 24 mg for 158 pts (66%), 20mg for 35 pts (15%) and lower for 47 pts. Median KM estimate of persistency on L was 15.8 mo and was similar for pts starting full or reduced dose. Treatment persistency was similar between all provinces but there was a trend favouring prescribers with more than one patient in the PSP versus those with only one patient (18.0 mo vs 10.2 mo, p = 0.0922) and for pts treated by endocrinologists compared to other specialties. There was also a trend for longer persistency in pts who had dose modifications compared to pts treated with constant doses (19.0 mo vs 9.8 mo, p = 0.0577). One hundred and twelve pts have discontinued L (39 deaths from disease, 23 progressive disease/palliation, 15 for medical reasons other than toxicity (including decision to pursue alternative therapy), 14 from toxicity and 21 undisclosed/other reasons).

Conclusions

To date, this is the largest presented real-world analysis of the treatment patterns of L in pts with rDTC and our estimates of treatment duration as proxy for effectiveness are comparable to the phase 3 SELECT trial. Toxicity led to a minor proportion of discontinuations.

Legal entity responsible for the study

The authors.

Funding

Eisai Supported the Patient Support Program, hosted by Innomar Strategies, Inc.

Disclosure

S.J. Hotte: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai. E. Winquist: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai. N. Chua: Honoraria (self), Advisory / Consultancy: Eisai. J..D. Ruether: Honoraria (self), Advisory / Consultancy: Eisai. N. Lamond: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai. S. Ezzat: Advisory / Consultancy: Eisai. M. Massicotte: Honoraria (self), Advisory / Consultancy: Eisai. R. Wong: Advisory / Consultancy: Eisai. P. Lam: Full / Part-time employment: Eisai. B. Yap: Full / Part-time employment: Eisai. M.K. Krzyzanowska: Honoraria (self), Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Exilixis. All other authors have declared no conflicts of interest.

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Poster Discussion – NETs and endocrine tumours Poster Discussion session

1864PD - Spatiotemporal intratumor genetic heterogeneity and clonal evolution in PTCs and paired DM (ID 5072)

Presentation Number
1864PD
Lecture Time
11:10 - 11:10
Speakers
  • Sara Gil Bernabé (Valladolid, Spain)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

Papillary Thyroid Carcinoma (PTC) represents 80% of all thyroid cancers. Though the vast majority of PTC are indolent tumors, around 15% behave aggressively, developing distant metastases (DM), which cause patient´s death. The molecular mechanisms underlying DM are poorly understood. Little it is known about the contribution of intratumor heterogeneity to DM. Dynamic changes in mutation distribution through space and time have not been in deep characterized.

Methods

By genotyping 13 cases of matched primary tumors (PrT) and DM, we sought to determine the prevalence of mutations in genes that have been associated with tumor progression and aggressiveness in follicular thyroid carcinogenesis. To assess the contribution of intratumor heterogeneity and clonal evolution to DM, 54 tumor areas, including different areas across space and time within the PrT and the DM were analyzed. Genotyping was approached by PCR and SSCP or DS.

Results

Twelve cases (92%) were mutated in at least one of the genes screened [TERT 69%, BRAF 54%, KRAS 23%, NRAS 23%, HRAS 15.4%, PIK3CA 15.4%]. No mutations were seen at MED12 or EIF1AX. Among the mutated cases 67% exhibited more than 1 gene activated. Three mutated genes co-existed in 62.5% of the cases. Concurrent activation of TERT+RAS or TERT+BRAF was seen in 5 cases each event (62.5%). Simultaneous activation of BRAF and RAS was found in 4 cases (50%). In all the cases in which more than 1 area of DM, across space and time, was analyzed, the mutations at TERT, KRAS and HRAS resulted clonal. De novo mutations at DM were seen in 6 cases. Within PrT, subclonality was as follows TERT 33%; RAS 20%; BRAF 40% and PIK3CA 100%.

Conclusions

The number of mutational events in PTC with DM is strikingly higher than in PTC without DM. While TERT and RAS mutations tend to be clonal within PrT and DM, BRAF mutations tend to be subclonal. TERT and RAS mutations may appear the novo at DM. PTC with DM display a much higher rate of genetic heterogeneity (67%). The coexistence of mutations in different genes is in agreement with the hypothesis that tumor progression relies on progressive accumulation of genetic alterations. MED12 and EIF1AX do not play a role in aggressive PTCs. Concurrent mutations at TERT, and different PI3K/AKT and MAPK pathway genes are common in metastatic PTC.

Legal entity responsible for the study

Ginesa García Rostán.

Funding

Head of Group "Pathobiology of Cancer: Inter-, Intra-tumoral heterogeneity and Molecular Targets at Institute of Molecular Biology and Genetics (IBGM) of Valladolid University.

Disclosure

All authors have declared no conflicts of interest.

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Poster Discussion – NETs and endocrine tumours Poster Discussion session

1865PD - Specific patterns of long non-coding RNA expression in benign and malignant thyroid nodules (ID 2034)

Presentation Number
1865PD
Lecture Time
11:10 - 11:10
Speakers
  • Valentina Yakushina (Moscow, Russian Federation)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30

Abstract

Background

Although there are increasing evidences of lncRNA role in cancer progression, and of its possible diagnostic and therapeutic significance, lncRNA in thyroid neoplasms are poorly investigated: studies are limited to papillary cancer, the differences in variants of papillary carcinoma are rarely considered, there are no investigations of lncRNA in benign nodules, follicular and anaplastic carcinomas.

Methods

To evaluate lncRNA expression in follicular adenoma (FA), follicular and classical variants of papillary carcinoma (fvPTC/clPTC), follicular (FTC) and anaplastic (ATC) carcinomas, a comprehensive dataset of 8 independent Microarray experiments on Affymetrix Human Genome U133 Plus 2.0 Array and RNA-Seq experiments (TCGA and PRJEB11591 projects) was analyzed. In silico validation of differential expression was performed. Putative functions of aberrantly expressed lncRNA were determined via co-expression and enrichment analysis of Gene Ontology, KEGG, Reactome terms.

Results

The analysis revealed 8 lncRNA general for all investigated neoplasms, 22 - general for papillary carcinomas, 32 - specific for clPTC, 1 - for fvPTC, and 177 - specific for ATC. No lncRNA differentially expressed in FTC and FA was found. There are strong clustering of ATC, clustering of clPTC and fvPTC, no clustering within the FTC and FA. LncRNA found to be specific for ATC are probably associated with anaplastic features and cancer progression. Potential functions of lncRNA general for all studied neoplasms - L1CAM interactions; general for papillary carcinomas - tryptophan metabolism; specific for fvPTC - cell polarity and WNT signaling; specific for clPTC - extracellular matrix organization and endoderm formation; specific for ATC - cell cycle and mitosis. Known oncogenic and tumor suppressor lncRNA (NR2F1-AS1, LINC00511, SLC26A4-AS1, CRNDE, LINC01116, RMST) are found in thyroid carcinomas for the first time.

Conclusions

Common and specific patterns of lncRNA expression in main histological subtypes of thyroid nodules are determined. The findings enhance the understanding of lncRNA in thyroid cancer progression.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Discussion – NETs and endocrine tumours Poster Discussion session

Invited Discussant 1862PD, 1863PD, 1864PD and 1865PD (ID 6892)

Lecture Time
11:10 - 11:25
Speakers
  • Sophie Leboulleux (VILLEJUIF, France)
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30
Poster Discussion – NETs and endocrine tumours Poster Discussion session

Q&A led by Discussant (ID 6895)

Lecture Time
11:25 - 11:30
Location
Cartagena Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:30 - 11:30