1184MO - Safety and efficacy of everolimus (EVE) as second-line treatment in neuroendocrine neoplasms G3 (NEN G3): An AIO phase II study (EVINEC)

Background

Well-differentiated neuroendocrine tumors G3 (NET G3) represent a separate entity from poorly differentiated neuroendocrine carcinoma (NEC). While platinum-based 1^st- line chemotherapy is established in advanced NEC, there is limited efficacy of 2^nd- line chemotherapies, and therapy of NET G3 is still under investigation. Since the mTOR inhibitor everolimus mediates disease stabilization in patients with NET G1/G2, and data on targeted therapy in NEN G3 were lacking, we investigated EVE as 2^nd- line treatment in NEN G3.

Methods

EVINEC was a prospective, single-arm, phase 2 study planned to enroll 40 patients with histologically confirmed NET G3 or NEC G3 with progressive disease on or after platinum-based chemotherapy. Treatment was EVE at 10 mg/day. The primary endpoint was safety; efficacy measurements were secondary endpoints. Central pathology review was performed by a highly experienced pathologist.

Results

Thirty-nine patients were initially found eligible. For three of these, central review determined their tumors not to be NEN. Of the remaining 36, 13 were NET G3, 14 NEC, and 9 mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN). MiNEN patients remained on study since NEN components were NEC G3. Most frequent EVE-related adverse events were stomatitis (39%), fatigue (31%), diarrhea (28%), nausea (25%), decreased appetite (22%), epistaxis (19%), rash (19%), decreased weight (17%), back pain (14%), dry mouth (14%), aphthous ulcer (11%), dermatitis acneiform (11%), and pyrexia (11%). Two patients (6%) were affected by pneumonitis, and treatment-related infections were reported for 5 patients (14%). Median PFS and OS for the Per Protocol (PP) population were 2.2 and 12.0 mo., in NET G3 5.2 (range 0.7-18.8) and 23.9 mo., in NEC 1.8 and 5.6 mo., and in MiNEN 2.2 and 7.0 mo., respectively. Six patients were excluded from the PP set due to short treatment duration or lack of efficacy assessment.

Conclusions

No clinically relevant safety signals for EVE after prior platinum-based therapy in NEN G3 were identified. The data support efficacy in NET G3 but insufficient activity in NEC or MANEC. More data are warranted from prospective trials in NET G3 to address EVE efficacy compared to other treatments.

Clinical trial identification

EudraCT 2012-004550-28.

Editorial acknowledgement

Medical writing support was provided by Frauke Meyer, CORBIN GmbH, Berlin. The support was funded by the study Sponsor AIO-Studien-gGmbH.

Legal entity responsible for the study

AIO-Studien-gGmbH, Berlin.

Funding

Novartis.

Disclosure

M.E. Pavel: Financial Interests, Personal, Invited Speaker: Ipsen, AAA, Boehringer Ingelheím, Lilly; Financial Interests, Personal, Advisory Board: AAA, Amgen, Riemser; Financial Interests, Institutional, Advisory Board: Crinetics; Financial Interests, Personal, Other, study analysis: Hutchmed; Financial Interests, Personal, Invited Speaker, Speaker at meetings: MSD; Financial Interests, Institutional, Local PI, fees for study conduct: Novartis; Financial Interests, Institutional, Local PI, Fees for study conduct: ITM; Financial Interests, Institutional, Coordinating PI, Fees for coordinating PI: Ipsen; Financial Interests, Institutional, Steering Committee Member: AAA; Financial Interests, Institutional, Local PI: AAA; Non-Financial Interests, Advisory Role, speaker at meetings, advisor for projects: Patient support group Netzwerk NET, Germany and INCA; Non-Financial Interests, Leadership Role, Past president, currenct vice president: European Neuroendocrine Tumor Society - ENETS; Non-Financial Interests, Other, Member of EMSO Education Group, Participation in PG course and other educational activities; member of the NET track steering committee group for ESMO Annual Meetings: ESMO. All other authors have declared no conflicts of interest.