Everolimus after Transarterial Liver Therapy of Metastases from Gastrointestinal Neuroendocrine Tumors: the FFCD 1104-EVACEL-GTE Phase II Study.

Background: Transarterial liver therapy (TALT) is indicated in the treatment of isolated or predominant progressive liver metastases of gastrointestinal neuroendocrine tumors (GI-NETs). TALT increases circulating VEGF levels. Everolimus is an approved systemic treatment in NETs that has anti-angiogenic activities. Our hypothesis is that everolimus may increase hepatic progression-free survival (hPFS) 24 months after TALT. Methods: EVACEL is a single arm phase II multicenter prospective study conducted in patients with predominant and progressive liver metastases within previous 12 months from well-differentiated grade 1-2 GI-NETs. Everolimus (10 mg/day) was started 7 days after TALT, once liver toxicity was grade ≤1. The primary endpoint was the hPFS rate at 24 months (≥35% is sufficient to demonstrate efficacy, 50% is expected) based on the central review assessment. Results: The characteristics of the 77 enrolled patients were female 42%, median age 66 (range: 43-86) years, primary tumor in the small bowel 91%, grade G1 43%, G2 57%, extra-hepatic metastases 51%), median liver tumor burden 30% (range, 1-80), and previous somatostatin analog treatment 74%. Patients underwent 1 (n = 19), 2 (n = 54) or 3 (n = 1) TALT: bland (n = 21) or chemo-embolization (n = 109). Sixty-seven (87%) pts were eligible for everolimus. Forty (54%) and 30 (41%) pts had objective response (RECIST 1.1) and stable disease, respectively (1 pt was not evaluable). Median (IC 95%) PFS and overall survival were 16.9 (12.6-22.3) and 44.6 (29.1-not reached) months, respectively. The most common grade 3-4 toxicities (>5%) in patients receiving both TALT and everolimus (n = 67) were the post-TALT syndrome (55%), fatigue (18%), diarrhea (16%), anemia (12%), cutaneous (9%), hypertriglyceridemia (7.5%) and mucositis (6%). The primary endpoint will be presented at the meeting. Conclusions: Everolimus can be safely administered following TALT. Results of this sequence of therapies are encouraging. Clinical trial identification: NCT01678664. Editorial acknowledgement: Novartis Pharma AG provided an unrestricted research grant. Legal entity responsible for the study: FFCD. Funding: FFCD. Disclosure: T. Walter: Congress, advisory board, research: Novartis, Ipsen, Keocyt, AAA. C. Lepage: Research: Ipsen Pharma, Novartis Oncology; Speaker: Advanced Accelerator Applications; Travel, accomodations: Amgen, Ipsen Pharma, Novartis Oncology, Bayer. R. Coriat: Consulting or advisory role: Keocyt, Pfizer, Novartis, Roche, Merck, Amgen, Bayer; Research funding: Amgen, Novartis, Ipsen; Travel, accomodations, expenses: Ipsen, Amgen, Bayer. G. Cadiot: Honoraria: Ipsen, Novartis, Pfizer, AAA, Keocyt; Consulting or advisory role: Ipsen, Novartis, Pfizer, AAA, Keocyt; Research funding: Ipsen, Novartis. F.X. Caroli Bosc: Honoraria: Ipsen, Novartis, Lilly, Amgen. T. Aparicio: Honoraria: Shire, Roche, Servier, BMS, Amgen, Léo Pharma; Consulting or advisory role: BMS, Halio DX; Research funding: Novartis; Travel, accomodations, expenses: Roche, Hospira, Ipsen. K. Bouhier Leporrier: Honoraria, boards and congress: Ipsen and Novartis. C. Lepere: Consulting or advisory role: Novartis, Ipsen; Travel, accomodations, expenses: Ipsen, Novartis, Amgen. T. Lecomte: Consulting or advisory role, research funding, travel: Novartis; Consulting or advisory role, Travel: Ipsen. D. Smith: Speaker’s bureau: Novartis; Consulting or advisory role: Novartis, Pfizer. C. Petorin: Travel, accomodations, expenses: Novartis. M.P. Ducreux: Grants/research supports: Roche, Chugai, Pfizer; Honoraria or consultation fees: Roche, Celgene, Merck Serono, Amgen, Novartis, Sanofi, Pfizer, Lilly, Servier; Spouse: Head of BU, Sandoz. C. Lombard Bohas: Consulting or advisory role: Ipsen, Novartis, Pfizer, Advanced Accelerator Applications. T. de Baere: Consulting or advisory role, speaker’s bureau: Guerbet. All other authors have declared no conflicts of interest.