1143P - Ph II study of BEZ235 in patients with advanced pancreatic neuroendocrine tumors (pNET) after mTOR inhibitor therapy failure: Stage I interim results

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer Agents
Neuroendocrine Tumours
Biological Therapy
Presenter Nicola Fazio
Citation Annals of Oncology (2014) 25 (suppl_4): iv394-iv405. 10.1093/annonc/mdu345
Authors N. Fazio1, R. Buzzoni2, E. Baudin3, L. Antonuzzo4, R. Hubner5, H. Lahner6, W.W. De Herder7, M. Raderer8, A. Teule9, J. Capdevila10, S. Libutti11, M. Kulke12, M. Shah13, D. Dey14, S. Turri15, P. Aimone16, C. Verslype17
  • 1Unit Of Gastrointestinal And Neuroendocrine Tumors, Istituto Europeo di Oncologia IEO, 20141 - Milan/IT
  • 2Medical Onology, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milano/IT
  • 3Oncologie, Institut Gustave Roussy, Villejuif/FR
  • 4Medical Oncology, Azienda Ospedaliero Universitaria Careggi, Florence/IT
  • 5Medical Oncology, The Christie Hospital NHS Foundation Trust, M20 4BX - Manchester/GB
  • 6Clinic For Endocrinology, University of Duisburg-Essen, Essen/DE
  • 7Endocrine Oncology, Erasmus MC, Rotterdam/NL
  • 8Department Of Oncology, University Hospital of Vienna, Vienna/AT
  • 9Medical Oncology, Institut Català d'Oncologia, Barcelona/ES
  • 10Endocrine And Gastrointestinal Oncology, Vall d'Hebrón University Hospital, Barcelona/ES
  • 11Department Of Oncology - Surgery, Montefiore Medical Center and Albert Einstein College of Medicine, New York/US
  • 12Gastrointestinal Cancer, Dana–Farber Cancer Institute,, Boston/US
  • 13The James Cancer Hospital And Solove Research Institute, The Ohio State University, Columbus/US
  • 14Oncology, Novartis Healthcare Pvt Ltd, Hyderabad/IN
  • 15Oncology Global Development, Novartis AG, Basel/CH
  • 16Novartis Ag, Novartis AG, Basel/CH
  • 17Department Of Hepatology, KU Leuven, Leuven/BE



The mTOR inhibitor everolimus is approved for the treatment of patients with advanced pNet but resistance can occur. BEZ235 (BEZ) is an oral, dual inhibitor that targets class I PI3K and downstream effectors mTORC1/2. Here we present interim Stage I (open-label, single-arm) results of a multicenter, 2-stage, Ph II study of BEZ in patients with advanced pNET that had progressed on everolimus (NCT01658436).


Patients with unresectable/metastatic histologically confirmed low/intermediate-grade pNET with radiologic evidence of disease progression since last treatment and refractory to everolimus were enrolled. The starting dose of BEZ was 400 mg twice daily (BID), which was reduced to 300 mg BID due to the safety/tolerability profile. The primary objective of Stage I was to evaluate the efficacy of BEZ based on the progression-free survival (PFS) rate at 16 weeks (RECIST v1.1). Futility was shown if the observed 16-week PFS rate was <60% or the posterior probability that the PFS rate at 16 weeks was ≥40% was <90% for enrolled patients. Tumor responses were assessed every 8 weeks until disease progression or initiation of new therapy.


Between Nov 2012 and Sep 2013, 31 patients were enrolled and treated with BEZ 300 mg BID (n = 20) or 400 mg BID (n = 11). Median duration of exposure was 16 (range: 2–43) weeks. Seven patients were ongoing at data cut-off on Jan 16, 2014; the most common reason for discontinuation was adverse events (AEs; 39%) followed by progressive disease (36%). The 16-week PFS rate was 48% (90% CI 33–64), and the posterior probability that the PFS rate was ≥40% was 82%. Stable disease (SD) was achieved by 15 patients at Week 16 and 9 patients had progressive disease. The most frequent (≥10%) Grade 3/4 AEs regardless of causality were hyperglycemia (36%), and diarrhea, nausea, and gamma-glutamyltransferase increase (18% each) at BEZ 400 mg, and hyperglycemia (10%) at BEZ 300 mg.


At 400 mg, BEZ was not tolerated in this patient population who had progressed on everolimus; 300 mg/day was better tolerated, with most AEs being mild to moderate. Preliminary evidence of activity was observed, with 48% of patients achieving SD after 16 weeks of treatment. Due to high discontinuation of treatment due to AEs and early disease progression, the primary objective of Stage I was not met and the study will not proceed to Stage II.


N. Fazio: Advisory board for Novartis, Ipsen, Pfizer, Lexicon; R. Buzzoni: Received grants from: Novartis, Italfarmaco, Ipsen; E. Baudin: Advisory board/honoraria from Novartis, Ipsen, Pfizer, Roche; R. Hubner: A member of remunerated Novartis sponsored advisory boards; H. Lahner: Lectures: Novartis, Pfizer Grant received: Novartis Advisory board: Novartis, Pfizer; W.W. De Herder: Participated in advisory boards for Novartis and Ipsen; M. Raderer: Received honoraria from: Novartis, Roche, Ipsen, Pfizer, Bayer, Celgene; A. Teule: Data monitoring board for the Catalan Institute of Oncology, and received grants and personal fees from Novartis; M. Kulke: Consulted for Novartis; M. Shah: Received research funding from Novartis; D. Dey: Employee of Novartis; S. Turri: Employee of Novartis; P. Aimone: Employee of Novartis; Verslype: Received research funding from Novartis. All other authors have declared no conflicts of interest.