Phase II study of everolimus (EVL) and octreotide (OCT) LAR in patients with non-functioning gastrointestinal neuroendocrine tumours (GI-NETs): EVERLAR study

Abstract

Background: Anti‐tumour activity of the combination of somatostatin analogues (SSA) and the mTOR inhibitor EVL in patients ( pts) with NETs has been suggested but not confirmed in prospective trials. Methods: The prospective multicentre single‐arm phase II EVERLAR study was conducted to explore the anti‐tumour activity of EVL 10 mg/d and OCT 30 mg q28d in pts with advanced non‐functioning well‐differentiated GI‐NETs that progressed in the last 12 months. Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Pts continued treatment until progression or unacceptable adverse events (AEs). Primary endpoint was progression‐free survival (PFS) at 12 months; secondary endpoints included PFS by Kaplan‐Meier (KM), early biochemical response (> 30% decrease at week 4), objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression). Results: Of the 44 pts enrolled (24 [54.5%] male, 32 [72.7%] ECOG PS 0), 43 were included in the ITT analyses (1 excluded due to pancreatic origin). Primary tumour location was foregut (11.6%), midgut (48.8%), hindgut (11.6%), unknown (27.9%). Prior SSA was received in 86.1% of pts. After 12 months of treatment, 62.8% (CI95%: 48‐77%) of pts in the ITT population had not discontinued, progressed or died. Median PFS was 11.5 months. Early biochemical response was reported in only 6 pts (14%). ORR was 4.7% and stable disease was 83.7%. Median OS was not reached after 24 months of median follow‐up (mean 33 months, CI95%:27.7‐40 months). Dose reductions and temporary interruptions due to EVL side effects were required in 4 (9%) and 20 (45.5%) pts, respectively. Most frequent AEs were low platelet count (10 pts, 22.7%), anaemia (7 pts, 15.9%), hyperglycaemia (6 pts, 13.6%), hypophosphatemia (3 pts, 6.8%). No correlation was observed between IGFR1 and pS6 expression and OS (p = 0.105, Log rank Test). Conclusions: The EVL‐OCT combination provided clinically relevant efficacy in non‐functioning GI‐NETs similar to the results of RADIANT‐2 in functioning setting.