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)

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 Espanol 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. Teule: 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.